Ageing Research Reviews 91 (2023) 102077

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Ageing Research Reviews

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Review

Ferroptosis in Parkinson’s disease: Molecular mechanisms and

therapeutic potential
Xv-shen Ding a, b, 1, Li Gao a, 1, Zheng Han a, 1, Simona Eleuteri c, Wei Shi d, Yun Shen a,
Zi-yao Song b, Mingming Su a, Qian Yang e, Yan Qu a, *, David K. Simon c, *, Xue-lian Wang a, *,
Bao Wang a, *
a
Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, 710038, China
b
Basic Medicine School, The Fourth Military Medical University, Xi’an, Shaanxi Province, 710038, China
c
Department of Neurology, Beth Israel Deaconess Medical Center, 3 Blackfan Circle 628H, Boston, MA 02215, USA
d
Department of Neurosurgery, PLA 960th hospital, JiNan, Shandong Province, 250031, China
e
Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, 710038, China

A R T I C L E I N F O A B S T R A C T

Keywords: Parkinson’s Disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra
Ferroptosis (SN), leading to motor and non-motor symptoms. While the exact mechanisms remain complex and multifaceted,
Parkinson’s Disease several molecular pathways have been implicated in PD pathology, including accumulation of misfolded pro­
Neuronal death
teins, impaired mitochondrial function, oxidative stress, inflammation, elevated iron levels, etc. Overall, PD’s
Clinical trials
Oxidative stress
molecular mechanisms involve a complex interplay between genetic, environmental, and cellular factors that
disrupt cellular homeostasis, and ultimately lead to the degeneration of dopaminergic neurons. Recently,
emerging evidence highlights ferroptosis, an iron-dependent non-apoptotic cell death process, as a pivotal player
in the advancement of PD. Notably, oligomeric α-synuclein (α-syn) generates reactive oxygen species (ROS) and
lipid peroxides within cellular membranes, potentially triggering ferroptosis. The loss of dopamine, a hallmark of
PD, could predispose neurons to ferroptotic vulnerability. This unique form of cell demise unveils fresh insights
into PD pathogenesis, necessitating an exploration of the molecular intricacies connecting ferroptosis and PD
progression. In this review, the molecular and regulatory mechanisms of ferroptosis and their connection with
the pathological processes of PD have been systematically summarized. Furthermore, the features of ferroptosis
in PD animal models and clinical trials targeting ferroptosis as a therapeutic approach in PD patients’ man­
agement are scrutinized.

1. Introduction ventrolateral tier of the SNpc may be responsible for many of the
motor-related symptoms (Dickson et al., 2009). However, while α-syn­
Parkinson’s disease (PD) is the second most common neurodegen­ uclein (α-syn) deposition, iron accumulation, neuroinflammation, and
erative disease. Its clinical symptoms are divided into motor and non- oxidative stress are considered risk factors, the mechanisms of dopa­
motor, with motor-related symptoms including resting tremor, rigid­ minergic neuronal death still are not fully elucidated (Dionísio et al.,
ity, bradykinesia, and postural instability, and non-motor symptoms 2021; Nalls et al., 2014).
including sleep disturbances, autonomic nervous system dysfunction, In part because the pathological mechanisms of PD are not fully
cognitive impairment, and gastrointestinal symptoms, among others understood, existing therapies can only relieve symptoms but not block
(Kalia and Lang, 2015). Two aspects of PD pathology are: loss of progression of neurodegeneration. Levodopa (L-DOPA), the most effec­
dopaminergic neurons in the substantia nigra pars compacta (SNpc), and tive drug for PD patients, combined with aromatic acid decarboxylase
the emergence of Lewy bodies. Loss of dopaminergic neurons in the inhibitors such as carbidopa or benserazide, can greatly improve motor

* Corresponding authors.
E-mail addresses: [email protected] (Y. Qu), [email protected] (D.K. Simon), [email protected] (X.-l. Wang), [email protected]
(B. Wang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.arr.2023.102077
Received 26 June 2023; Received in revised form 26 August 2023; Accepted 21 September 2023
Available online 24 September 2023
1568-1637/© 2023 Elsevier B.V. All rights reserved.
X.-s. Ding et al. Ageing Research Reviews 91 (2023) 102077

symptoms (Jankovic and Tan, 2020). However, L-DOPA treatment is 2. Ferroptosis - a unique form of death driven by lipid
associated with side effects as the drug dose increases, such as ortho­ peroxidation
static hypotension, sedation, hallucinations, and dyskinesias. Moreover,
nearly half of patients experience wearing-off of the benefits between 2.1. Definition of ferroptosis
doses within two years of L-DOPA treatment (Jankovic and Tan, 2020).
Young-onset PD patients on L-DOPA therapy are more likely to develop Ferroptosis is a unique form of cell death first proposed in 2012 (Yan
motor fluctuations and dyskinesias (Mehanna and Jankovic, 2019). et al., 2021). Different from apoptosis, autophagy, necrosis, and
Anticholinergics such as trihexyphenidyl and benztropine can alleviate pyroptosis, ferroptosis is described as an iron-dependent and regulated
tremors but are less helpful for bradykinesia, and their anti-cholinergic form of cell death driven by lipid peroxidation (Stockwell et al., 2017).
effects may cause side effects such as exacerbation of constipation and The occurrence of ferroptosis results from the accumulation of LOOHs to
cognitive impairment, limiting their widespread use (Fox et al., 2018). toxic levels (Stockwell, 2022). In vitro, ferroptosis can be reversed by
Dopamine receptor agonists are associated with a lower risk of dyski­ iron chelators and lipophilic antioxidants (Friedmann Angeli et al.,
nesias compared to L-DOPA. They can be used independently for the 2014). Cells undergoing ferroptosis usually exhibit necrotic-like
treatment of motor symptoms or as adjunctive therapy when L-DOPA morphological transformation, including cell membrane rupture, cyto­
does not adequately control symptoms. However, these drugs are asso­ plasmic swelling, and moderate chromatin condensation (Tang et al.,
ciated with a significant risk of impulse-control disorders such as path­ 2021). The organelle which is mainly altered during ferroptosis is the
ological gambling, compulsive shopping, hyperphagia, hypersexuality, mitochondria, as evidenced by mitochondrial shrinkage, increased
and others (Warren et al., 2017). Amantadine has an anti-glutamatergic membrane density, reduced or absent cristae, and rupture of the outer
effect and anticholinergic properties, which make it the main drug to membrane (Li et al., 2020a). Also, autophagy-related structures such as
and can be used to treat tremors and L-DOPA-related dyskinesias (Rascol double-membrane autophagosomes and lysosome-associated vesicles
et al., 2021), but like other medications it can have side effects, and its often are observed in ferroptosis cells (Chen et al., 2021a). In the last
efficacy for other aspects of parkinsonism is limited. In addition to decade, although many issues are still being elucidated, the mechanisms
medications, deep brain stimulation surgery is effective in relieving of ferroptosis and its role in pathophysiological processes have been
some PD motor symptoms, but still cannot stop the progression of the gradually revealed (Fig. 1).
disease. Taken together, the current treatment strategies for PD have
shortcomings and none address the underlying disease pathophysiology. 2.2. Molecular mechanisms of ferroptosis
Early in 1982, Ursini et al. found that glutathione peroxidase 4
(GPX4) inhibited the conversion of toxic lipid hydroperoxides (LOOHs) Dysregulation of iron metabolism is a key trigger for ferroptosis. The
to non-toxic lipid alcohols (LOHs) and avoided plasma membrane imbalance between iron input, storage, and output may affect cellular
damage (Ursini et al., 1982). In 2003, Dolma et al. found a new susceptibility to ferroptosis. Intracellular iron is increased by enhanced
genotype-selective anti-tumor agent erastin, which can initiate a special iron input within transferrin (Tf) via the Transferrin receptor (TfR) and
form of non-apoptotic cell death (Dolma et al., 2003). Another com­ increased ferrous ions (Fe2+) input via divalent metal transporter pro­
pound, RSL3 (RAS-selective lethal 3), was reported in 2008 that also tein 1 (DMT1) (Rogers et al., 2019). Iron export is largely dependent on
induces a similar form of cell death dependent on an increase in the the cell surface iron transporter protein (FPN) and can be inhibited by
labile iron pool (LIP) (Yang and Stockwell, 2008). At the same time, FPN through β-amyloid precursor protein (APP) or ceruloplasmin (CP)
other studies showed that deficiency of GPX4 expression induces lipid (Hare et al., 2013; McCarthy et al., 2014; Wang and Wang, 2019).
peroxidation and also leads to non-apoptotic cell death, which could be Elevated pools of unstable iron catalyzes the formation of phospholipid
prevented by overexpression of the Xc- system (Banjac et al., 2008; hydroperoxides (PLOOHs). Studies have shown that exosomes can
Seiler et al., 2008). In 2012, the concept of ferroptosis was proposed to decrease intracellular iron levels (Chen et al., 2020). Ferritinophagy is a
name this unique form of cell death. Ferroptosis subsequently was found newly defined autophagy process associated with iron metabolism. The
to be related to many other cell activities, including mitophagy, plasma nuclear receptor coactivator 4 (NCOA4) binds to ferritin in autophago­
membrane disruption, and carcinogenesis (Dixon et al., 2012). Mean­ somes and leads to autophagy degradation (Dixon et al., 2012). Ferri­
while, with the discovery of the crucial role of ferroptosis in metabolism, tinophagy regulates the abundance of free iron by regulating ferritin
reactive oxygen species (ROS) biology, and iron metabolism, it was levels (Gao et al., 2019; Hou et al., 2016). Free cytoplasmic Fe2+ con­
further defined as an iron-dependent and regulated form of cell death stitutes the LIP which participates in the Fenton reaction, producing
driven by lipid peroxidation, in contrast to previously known forms such highly reactive hydroxyl radicals (⋅OH) from hydrogen peroxide (H2O2)
as apoptosis, autophagy, necrosis, and pyroptosis (Dixon et al., 2012). (Dixon and Stockwell, 2014). The process by which free polyunsaturated
Ferroptosis is characterized by iron-dependent lipid peroxidation, and fatty acids (PUFA) participates in the formation and peroxidation of
oxidative stress. Interestingly, Biondetti et al. revealed that an increase plasma membrane requires the catalysis of iron-cofactor enzymes. The
in iron content is correlated with SNpc neuronal loss and striatal conversion of membrane phospholipids to PLOOHs catalyzed by
dysfunction (Biondetti et al., 2021). Aggregation of α-syn also is related arachidonate lipoxygenases (ALOXs) requires iron utilization mediated
to iron, calcium, and lipid peroxidation (Angelova et al., 2020). As for by phosphorylase kinase G2 (PHKG2) (Yang et al., 2016). Another iron
oxidative stress, it is an important known cause of neuronal loss (Dio­ cofactor enzyme, cytochrome P450 oxidoreductase (POR), also is a key
nísio et al., 2021). All these characteristics suggest a potential associa­ regulator of ferroptosis and is involved in lipid peroxidation (Zou et al.,
tion between ferroptosis and PD, which may provide new targets for PD 2020b).
treatment. Ferroptosis is driven by lipid peroxidation. Not all lipids can
In this review, we first systematically summarize ferroptosis’s participate in the peroxidation process, and the occurrence of peroxi­
mechanisms and their role in PD pathogenesis. In addition, we dation depends on the stability of C-H bonds. Only specific carbon atoms
enumerate the association of PD-associated pathogenic proteins with in lipids are vulnerable to peroxidation because the reaction involves the
ferroptosis. Finally, we review the clinical studies and future perspec­ substitution of the peroxyl group (O-O) for the hydrogen atom attached
tives regarding ferroptosis and ferroptosis modulators in PD. to the carbon atom; therefore, the propensity of lipids to undergo per­
oxidation depends on the strength of their carbon-hydrogen bonds.
Among the various membrane phospholipids, phosphatidylethanol­
amine (PE) and phosphatidylcholine (PC), which contain arachidonic
acid (AA) and adrenic acid (ADA), are the main targets of lipid peroxi­
dation (Kagan et al., 2017; Yang and Stockwell, 2016). There are weak

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Fig. 1. The primary mechanisms of ferroptosis. (1) Intracellular iron is increased by enhanced iron input within Tf via the TfR and increased Fe2+ input via DMT1.
Iron export is largely dependent on the cell surface FPN and can be inhibited by FPN through APP or CP. Elevated pools of unstable iron catalyze the formation of
PLOOHs. The free cytoplasmic Fe2+ that constitutes the LIP participates in the Fenton reaction, producing highly reactive •OH from H2O2. (2) Activated PUFA is
incorporated into membrane lipids and leads to lipid peroxidation. ACSL4 and LPCAT3 bind PUFA to the plasma membrane and activate PUFA in the form of the PL•,
and PL⋅ is transformed into PLOOHs by 12/15-LOXs. ACSL4 can be inhibited by E-cadherin and PKCβII. Conjugated linolenic acids produced by some plants (e.g.,
α-eleostearic acid) require ACSL1 for their ferroptosis induction, and MUFAs require ACSL3 for their anti-ferroptosis effects. PLOOH reacts with Fe2+ to generate
PLOO•. (3) Mitochondria are the main source of endogenous ROS in cells. VDAC, located in the mitochondrial outer membrane, affects ferroptosis by regulating
oxidative stress. (4) GPX4 is the regulatory center of ferroptosis. Cystine is imported by XCT and then combined with glutamate to transform GSH, which generates
GPX4 in subsequent steps. The XCT can be blocked by sulfasalazine. Another source of cystine is synthesized by methionine; DJ-1 plays a vital role in this process.
Erastin and RSL3 are two ferroptosis-inducing compounds, one of which prevents cystine import by inhibiting XCT, and the other acts by inhibiting GPX4.
Meanwhile, other mechanisms by which GSH depletion sensitized cells to ferroptosis include: the multi-drug resistance gene MDR1 which enhances sensitivity to
ferroptosis by regulating GSH production. The cysteine catabolic enzyme cysteine dioxygenase1 (CDO1) reduces GSH levels by consuming cysteine. FIN56 was
obtained by recombining the molecular structure of CIL56 and plays a role in mediating GPX4 depletion. FIN56 can also increase the sensitivity of cells to ferroptosis
by depleting CoQ10. (5) CoQ10 is another endogenous mechanism of lipid peroxidation against ferroptosis. CoQ10 is found in mitochondria and different types of
cell membranes. FSP1 regenerates CoQ10-H2 by depleting NADPH. CoQ10-H2 scavenges lipid peroxidation intermediates and is then oxidized. At the same time,
NADPH is consumed to regenerate CoQ10-H2. DHOH is a kind of mitochondrial protein located on the outer surface of the inner mitochondrial membrane, it can also
promote the conversion of CoQ10 to CoQ10-H2 and participate in the regulation of lipid peroxidation in ferroptosis. FSP1 exerts similar function like DHOH. (6)
GCH1 produces the lipophilic antioxidant BH4 to prevent lipid peroxidation, which functions similarly to CoQ10. GCH1 can also mediate the remodeling of the lipid
membrane environment to increase the abundance of CoQ10-H2 while depleting PUFA phospholipids, an inducer of ferroptosis.

C-H bonds between the adjacent C– – C double bonds in PUFAs, which mechanisms of ferroptosis caused by LPCAT3 null cells (Reed et al.,
makes them more sensitive to this process (Stockwell, 2022). The 2022). It should be noted that not all PUFA phospholipids can increase
occurrence of PUFAs induced ferroptosis involves two steps: (1) Free the cells’ susceptibility to ferroptosis. The PUFA phospholipids with an
PUFAs are activated and incorporated into the plasma membrane (the adrenyl (C22:4) or arachidonyl (C20:4) are more sensitive oxidation
formation of PUFA phospholipids); (2) The peroxidation of PUFA substrates for ferroptotic signals (Kagan et al., 2017). Oxidation of PUFA
phospholipids. The activation of free PUFAs requires the catalysis of phospholipids by iron-dependent 12/15-LOX promotes the accumula­
acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) tion of PLOOHs at the plasma membrane level (Wenzel et al., 2017).
and lysophosphatidylcholine acyltransferase 3 (LPCAT3) (Doll et al., Fenton reaction and free reactive radicals extract hydrogen atoms from
2017). Free cytoplasmic PUFAs bind to ACSL4, allowing PUFA-CoA the carbon chains of phospholipids to form lipid radicals (PL•). These
binding to phospholipids in the plasma membrane (Doll et al., 2017). radicals react rapidly with oxygen and form lipid peroxyl radicals
ACSL4 links free PUFAs to CoA to produce fatty acyl-CoA esters which (PLOO•), which can then react with neighboring lipids to propagate the
are ultimately incorporated into PC or PE by LPCAT3 (Dixon et al., production of new PLOO• and PLOOH (Girotti, 1998). The conjugated
2015). PE-AA and PE-ADA can be oxidized by lipoxygenases (LOXs). linoleates such as α-eleostearic acid (αESA) are regarded as ferroptosis
LOXs and PEs binding protein 1 (PEBP1) act together to induce lipid inducers. They bind to cellular lipids in a pathway similar to PUFAs and
peroxidation at the membrane (Shah et al., 2018). ACSL4 has been promote peroxidation. The main difference is that another enzyme,
demonstrated to be a key factor in ferroptosis execution. In a study of the ACSL1, assists αESA incorporation into neutral lipids (triacylglycerols)
KBM7 cell line, cells that induced the inactivation of ACSL4 and LPCAT3 (Beatty et al., 2021). ACSL3, another ACSL family enzyme, also is
developed resistance to the ferroptosis inducer RSL3 (Dixon et al., involved in the inhibition of ferroptosis by exogenous monounsaturated
2015). Doll et al. found that ACSL4 could enrich the long poly­ fatty acids (MUFAs). MUFAs can significantly reduce the susceptibility
unsaturated ω6 fatty acids on the cell membrane and affect the pro­ of membrane lipids to oxidation. This protective effect of MUFAs is
duction of GPX4 to trigger ferroptosis (Doll et al., 2017). Another study related to the inhibition of lipid ROS accumulation at plasma mem­
showed that some small molecular compounds caused the recoding of branes, and a reduction of PLOOH levels. In the absence of ACSL3,
PUFAs in human cells by inhibiting LPCAT3 and increasing the PUFA exogenous MUFAs also protected cells from apoptotic lipotoxicity
phospholipids with an adrenyl (C22:4), which may be one of the induced by saturated fatty acid accumulation (Magtanong et al., 2019).

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Mitochondrial dysfunction leads to increased production of ROS, regulatory pathways have been revealed. In the absence of GPX4, fer­
which may also lead to an increase in plasma membrane PLOOHs roptosis can be inhibited by Coenzyme Q10 (CoQ10) biosynthesis via
(Neishi et al., 2017). Mitochondria-induced ferroptosis has been re­ the mevalonate pathway or by activation of CoQ10 reductases such as
ported in cysteine deprivation-induced ferroptosis (CDI ferroptosis). Gao FSP1 (AIFM2) or dihydroorotate dehydrogenase (DHODH). FSP1 pre­
et al. found that cysteine deprivation leads to hyperpolarization of the vents ferroptotic death by catalyzing the regeneration of CoQ10 to its
mitochondrial membrane potential and accumulation of lipid peroxides. reduced form CoQ10-H2, which is a potent mitochondrial and lipid
This effect can be relieved by mitochondrial TCA cycle or electron peroxyl radical trapping antioxidant. DHODH was identified as an in­
transfer chain (ETC) inhibition, and glutaminolysis (glutamine meta­ hibitor of ferroptosis located in mitochondria, similar to the function of
bolism) blockage. The possible reason is that glutaminolysis products FSP1 in the outer mitochondrial membrane, acting by promoting con­
can provide fuel for TCA cycle. For example, α-ketoglutarate acid, a version of mitochondrial CoQ10 to CoQ10-H2 (Doll et al., 2019; Mao
downstream product of glutaminolysis and a metabolic product of TCA et al., 2021; Nguyen et al., 2020). GTP cyclohydrolase 1 (GCH1) is
cycle, can replace glutamine and increase lipid ROS production (Gao another GPX4-independent system, it mediates the remodeling of the
et al., 2019). Zou et al. conducted genome-wide CRISPR-Cas9 suppressor lipid membrane environment, thus increasing the abundance of
screens and found that genes involved in peroxisomal function regulate CoQ10-H2 and depleting PUFA phospholipids. GCH1 is also the
ferroptosis. In addition, H2O2 produced in peroxisomes, together with rate-limiting enzyme for the synthesis of tetrahydrobiopterin (BH4).
Fe2+, may lead to lipid peroxidation (Zou et al., 2020a). Another study BH4 can promote CoQ10 synthesis by converting phenylalanine to
reported that knockdown of lysosomal protein prosaposin mediates tyrosine, which is how it exerts antioxidant effects. And the recycling of
lysosomal iron and ROS accumulation and subsequent neuronal fer­ BH4 requires the participation of dihydrofolate reductase, so the dihy­
roptosis by triggering lipoxin formation (Tian et al., 2021). At the same drofolate reductase inhibition can work together with GPX4 inhibitors
time, the cycle of TfR1 from the Golgi to the cell membrane also may be to induce ferroptosis (Fanet et al., 2021; Kraft et al., 2020; Soula et al.,
a mechanism of ferroptosis (Feng et al., 2020). 2020).
Recently, several additional pathways that are relevant to ferroptosis
have been identified. Kung et al. reported that microsomal GSH S-
2.3. Regulatory mechanisms of ferroptosis transferase 1 (MGST1) inhibited lipid peroxidation by binding to ALOX5
in human pancreatic ductal adenocarcinoma (PDAC) cell lines, and the
We summarize several ferroptosis inhibition mechanisms as follows expression of MGST1 is associated with NFE2L2, the gene that codes for
(Fig. 2). LOOH is a key product in the process of ferroptosis, while nuclear factor erythroid 2-related factor 2 (Nrf2) (Kuang et al., 2021).
glutathione (GSH) can reduce LOOH to LOH in the presence of GPX4, The protein kinase C (PKC) can interact with Nrf2 to form the PKC/Nrf2
and produce glutathione disulfide (GSSG) (Bjørklund et al., 2020; Yang signaling pathway, which is important in suppressing ferroptosis.
et al., 2014). GPX4 is a GSH-dependent peroxidase, which is influenced Oxidative stress drives PKC to phosphorylate Ser40 of Nrf2, which leads
by a variety of factors, including RSL3, XCT, ML162, ML210, FIN56, and to the separation of Nrf2 from Keap1 and promotes the transcriptional
others (Dixon et al., 2015; Shimada et al., 2016; Vallerga et al., 2020). activity of Nrf2 on antioxidant genes to resist ferroptosis (Huang et al.,
GSH is mainly synthesized from glutamate and cysteine; 2002). A study of cardiomyocyte ferroptosis showed that the cardiac
glutamate-cysteine ligase (GCL) is also a precursor substance for the regulator prostaglandin E2 (PGE2) acting on the E-prostanoid 1 receptor
synthesis of GSH. Intracellular cysteine derives mainly from two path­ (EP1) receptor in cardiomyocytes, and activating the PKC/Nrf2
ways: extracellular uptake mediated by Xc- system and synthesized from signaling pathway to prevent ferroptosis (Wang et al., 2023).
methionine (Oestreicher and Morgan, 2019). Studies have shown that The transsulfuration (TSS) pathway is another cysteine-targeted
blocking the Xc- system with inhibitors such as erastin and sulfasalazine mechanism of ferroptotic death inhibition. TSS is involved in the
induces ferroptosis (Dixon et al., 2012; Koppula et al., 2021; Yang et al., intracellular synthesis of cysteine, and changes in cysteine metabolism
2020). Similarly, gene inactivation or small molecule-mediated inhibi­ are related to intracellular GSH levels. Analogously, the SlC7A11-
tion or degradation of GPX4 leads to ferroptosis in various cell pheno­ mediated cystine uptake not only promotes GSH synthesis but also
types. It is worth noting that iron in LIP is stored in the form of binding to promotes GPX4 protein synthesis (Zhang et al., 2022a). An unbiased
low molecular weight compounds such as GSH. When GSH is consumed, genome-wide siRNA screen showed that deletion of CARS (the
the Fe2+ is released and serves as a substrate for Fenton reactions, which cysteinyl-tRNA synthetase) inhibits erastin-induced ferroptosis by
can trigger ferroptosis (Patel et al., 2019). GPX4 previously was reported blocking system Xc-. At the same time, knockdown of CARS resulted in
to be central to the regulation of ferroptosis. However, additional the accumulation of cythionine, a metabolite of the TSS pathway.
However, inhibition of the TSS pathway re-sensitized cells to erastin,
even after CARS knockdown (Hayano et al., 2016). Another study found
that inhibition of mTORC1 is accompanied by decreased levels of GPX4
protein. mTORC1 compensates for the low efficiency and high energy
requirement of GPX4 synthesis by promoting GPX4 protein synthesis
through the Rag-mTORC1–4EBP signaling axis (Zhang et al., 2021b).
mTORC1 also increases sterol regulatory element-binding protein 1
(SREBP1)-mediated lipogenesis to help cells fight ferroptosis (Yi et al.,
2020). In a recent study about sporadic Alzheimer’s disease, researchers
found that apolipoprotein E (apoE) could suppress ferritinophagy by
activating PI3K/AKT pathway, thereby inhibiting ferroptosis (Belaidi
et al., 2022).

Fig. 2. Three fundamental characteristics of ferroptosis along with their

2.4. MicroRNAs and ferroptosis
respective regulatory pathways. (1) Iron dysregulation: Activation of the Nrf2
pathway can mitigate iron dysregulation, maintaining cellular iron homeostasis
and inhibiting iron-induced cell death. (2) Lipid peroxidation: Activation of the MicroRNAs (miRNAs) have emerged as pivotal orchestrators of a
Nrf2, CoQ10, GCH1/BH4, mTOR, TSS, or GPX4 pathway inhibits lipid peroxi­ wide range of cellular processes, playing integral roles in preserving
dation, leading to the suppression of ferroptosis. (3) Oxidative stress: Activation physiological equilibrium and contributing to the intricate pathogenesis
of the Nrf2, CoQ10, GCH1/BH4, or DHODH pathway reduces oxidative stress, of diverse diseases. In recent years, mounting evidence has illuminated
thus inhibiting ferroptotic processes. the role of miRNAs in steering the regulatory mechanisms of ferroptosis

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across various contexts, encompassing neurodegenerative disorders, facilitating FTH1 degradation, thereby intensifying iron release, lipid
cancer, tissue damage, and more (as summarized in Table 1). peroxidation, and ROS accumulation (as highlighted in studies by Hu
In the context of PD, miRNAs have been implicated in the modula­ et al., 2021b; Li et al., 2021b; Tian et al., 2020).
tion of synucleinopathy, the loss of dopaminergic neurons, and the
ensuing locomotor impairments (Jin et al., 2018; Su et al., 2019). 3. Role of ferroptosis in the pathogenesis of PD
Notably, within an in vitro model of PD induced by 1-methyl-4-phenyl­
pyridinium (MPP+), miR-221 has been observed to downregulate the Early in 1987, Dexter et al. reported altered brain PUFA composition,
expression of TfR2, thereby mitigating 1-methyl-4-phenyl-1,2,3,6-tetra­ elevated lipid peroxidation products, and increased iron content in
hydropyridine (MPTP)-induced ferroptosis (Asci et al., 2013). postmortem parkinsonian brain substantia nigra (SN) cells (Dexter et al.,
Furthermore, leveraging in vivo and in vitro models of 6-hydroxy­ 1987). Hirsch et al. also found increased iron and aluminum in the SN of
dopamine (6-OHDA)-induced PD, the introduction of miR-335 mimics the parkinsonian brain by X-ray microanalysis in 1991 (Hirsch et al.,
has been shown to lead to diminished levels of ferritin heavy chain 1 1991). In 1992, Sofic et al. compared GSH concentrations in brain tissue
(FTH1), a known suppressor of ferroptosis. FTH1 exerts its regulatory between PD patients and controls, and found that reduced GSH associ­
influence by selectively binding to NCOA4, subsequently inducing fer­ ated with oxidative stress (Sofic et al., 1992). In recent years, Bellinger
ritinophagy to degrade FTH1. Reduced FTH1 levels result in the accu­ et al. reported that GXP4 levels are significantly decreased in the SN of
mulation of free Fe2+ and a decrease in mitochondrial membrane post-mortem PD brains (Bellinger et al., 2011). Since the term ferrop­
potential. Consequently, miR-335 amplifies the ferroptotic process by tosis was proposed in 2012, the role of ferroptosis has been emphasized
in PD physiopathology (Fig. 3) (Dixon et al., 2012).
Table 1
MicroRNAs and ferroptosis in various diseases. 3.1. Ferroptosis susceptibility induced by PD pathological features
Ferroptosis MicroRNA Diseases
Increasing pieces of evidence has confirmed the involvement of
Promotion
miR-27a-3p esophageal cancer ferroptosis in the pathophygiology and progression of PD. The aggre­
miR-335 parkinson disease gation of α-syn has been reported to induce ferroptosis by interacting
miR-6852, miR-1184, miR-302a- lung cancer with membranes and accelerating lipid peroxidation. Oligomeric α-syn
3p produces ROS and induces lipid peroxidation within the membrane.
miR-30b-5p preeclampsia
miR-21–3p melanoma
Calcium influx and increased intracellular calcium ion levels are caused
miR-5096, miR-106a-5p breast cancer by direct integration of α-syn oligomers into the cytomembrane. Under
miR-182–5p, miR-378a-3p, miR- ischemia-reperfusion injury the influence of this pathological calcium signal, neurons undergo
214 excitotoxicity and ferroptotic death. One hypothesis is that oxidized
miR-93–5p polycystic ovary syndrome
lipids may recruit more oligomers to the membrane, and that oligomers
miR-214 liver cancer
miR-382–5p ovarian and breast cancer lead to greater membrane destruction and more calcium influx (Ange­
miR-150–5p diabetic cardiomyopathy lova et al., 2020). Another mechanism by which oligomers induce ROS
miR-9–5p sepsis-associated production and lipid peroxidation is iron-dependent, that is, dependent
encephalopathy on the Fenton reaction to produce free radicals (Deas et al., 2016;
miR-147a glioblastoma
miR-375 gastric cancer
Ludtmann et al., 2018). Whereas α-syn aggregation is an important
miR-140–5p obesity-induced cardiac injury feature of familial PD, α-syn is also a major component of Lewy Bodies,
miR-128–3p, miR-25–3p prostate cancer implying a vital role for ferroptosis in PD. Another feature of PD is the
miR-188–3p diabetic nephropathy death of dopaminergic neurons of the SNpc and the subsequent decrease
miR-545–3p thyroid cancer
in nigrostriatal dopamine levels (Samii et al., 2004). Possibly because
miR-138–5p diabetic retinopathy
miR-15a-3p, miR-539 colorectal cancer dopamine may be converted into reactive quinones, dopaminergic
miR-15a-5p acute myocardial infarction
miR-5627–5p acute spinal cord injury
miR-1287–5p, miR-144–3p osteosarcoma
miR-324–3p renal cell carcinoma
Inhibition
miR-522 gastric cancer
miR-3173–5p pancreatic cancer
miR-362–3p, miR-3202 liver cancer
miR-137, miR-130b-3p melanoma
miR-129–5p bladder cancer
miR-149 endotoxemia
miR-4291 cervical cancer
miR-125b-5p sepsis-associated acute lung
injury
miR-124–3p, miR-20a-5p, miR- ischemia-reperfusion injury
193b
miR-23a-3p, miR-706 acute myocardial infarction
miR-222 hepatitis B virus infection
miR-7–5p doxorubicin-induced cardiac
injury
miR-370 periodontitis
Fig. 3. Four main risk factors of ferroptosis in Parkinson’s disease. (1) Oligo­
miR-122–5p intracerebral hemorrhage meric α-syn induces calcium influx in the cytomembrane and mitochondria,
miR-760–3p ischemic brain injury which finally promotes ROS increase in mitochondria. Oligomeric α-syn par­
miR-4443 lung cancer ticipates in the Fenton reaction and produce free radical. (2) Dopamine targets
miR-367–3p autoimmune encephalomyelitis GPX4 to increase GPX4 stability and inhibits ROS production mediated by iron.
miR-10a-5p intervertebral disc degeneration (3) HNE is produced along with the process of lipid peroxidation and results in a
miR-212–5p traumatic brain injury decrease in dopamine levels. (4) Iron accumulation dysfunction promotes
miR-670–3p glioblastoma
oxidative stress and excess free radical production. (5) Aging regulates iron
miR-221 parkinson disease
metabolism and inhibits GPX4-related reactions.

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X.-s. Ding et al. Ageing Research Reviews 91 (2023) 102077

neurons are more susceptible to ferroptosis. Astrocytes help neurons (Rhodes et al., 2014). A study showed high levels of TfR2 in SN dopa­
withstand oxidative stress and protect them from iron toxicity by minergic neurons in PD patients’ brains, where iron accumulated
delivering pertinent transcripts and proteins via exosomes or micro­ (Mastroberardino et al., 2009). The TfRs include TfR1 and TfR2. How­
particles. Therefore, dysregulation of astrocyte-neuron connections may ever, given that TfR2 has a lower affinity for iron-loaded Tf, the trans­
play a role in the etiology of PD and other neurodegenerative illnesses port function is mainly performed by TfR1 (Kawabata et al., 2000; West
(Ishii et al., 2019). However, dopamine also is a strong inhibitor of et al., 2000). It was discovered that extracellular Tf-bound iron was
ferroptosis, and therefore reduced dopamine levels in PD also may make taken up and directed to mitochondria by human cells that had been
the cells more susceptible to ferroptosis. Wang et al. suggested that transfected with a TfR2-expression plasmid. In part, dopaminergic
dopamine targets GPX4 to increase GPX4 stability and inhibit ROS neurons colocalize Tf and TfR2 within mitochondria. Additionally, sig­
production mediated by iron (Wang et al., 2016). Ferroptosis also was nificant increases in iron and oxidized Tf were seen in dopaminergic
shown to be the predominant form of cell death in PD models con­ neurons in both an animal model of PD caused by the complex I-inhib­
structed through paraquat (PQ), rotenone, 6-OHDA, and MPTP (Wen itor rotenone and in brain tissues from people with PD. Thus, the
et al., 2020). PQ is neurotoxic and this neurotoxicity is associated with over-accumulation of iron in mitochondria by the Tf/TfR2 system may
cellular oxidative stress and neuroinflammation, which induces α-syn play a vital role in the development of PD.
aggregation (Mak et al., 2010; Manning-Bog et al., 2002). Regulating the distribution of iron to mitochondria in dopaminergic
Rotenone-induced apoptosis in SH-SY5Y cells has some characteristics neurons appears to be a key function of the Tf/TfR2 system (Mas­
of ferroptosis, which can be inhibited by ferrostatin-1 (fer-1) (Kabiraj troberardino et al., 2009). In PD, intracellular Tf is elevated.
et al., 2015). 6-OHDA also can induce ferroptosis in an in vitro model Down-regulated expression of TfRs in PD models also has been
using SH-SY5Y cells (Sun et al., 2020). Another study showed that MPP+ demonstrated to inhibit the degeneration of dopaminergic neurons
induced ferroptosis in Lund human mesencephalic (LUHMES) cells, (Milanese et al., 2021). Meanwhile, increased iron levels have been re­
which are immortalized dopaminergic neuronal precursor cells that can ported to correlate with expression levels of the iron importer DMT1 and
differentiate into dopaminergic neurons (Zhang et al., 2014). These iron exporter FPN-1 in cellular models of PD like MPTP and 6-OHDA
studies demonstrate the important role of ferroptosis in the patho­ (Song et al., 2010; Yanatori and Kishi, 2019; Zhang et al., 2009). The
physiological mechanisms of relevance to PD. APP can bind to FPN-1 and increase its ability to facilitate iron export,
whereas APP expression is reduced in the SN of PD patients, resulting in
3.2. Iron dysregulation in ferroptosis and PD an iron-related phenotype similar to APP knockout mice (Belaidi et al.,
2018). CP is a copper transport protein that assists with iron export
Abnormal iron metabolism, as a common pathological feature of mediated by FPN-1 (Wang and Wang, 2019). Several studies have shown
ferroptosis and PD, serves as a bridge between the two. Iron is involved reduced CP levels in PD patients, together with iron accumulation and
in a myriad of vital processes in the central nervous system including the related oxidative stress in the SN, particularly in patients with the AT
neurotransmitter synthesis, oxygen transportation, myelin synthesis, genotype of the CP gene (Dusek et al., 2015; Hochstrasser et al., 2005).
and oxidative phosphorylation (Ferreira et al., 2019). Iron metabolism A criticial focus of PD research is the development of disease-
dysfunction may produce⋅OH which induces the oxidation and modifi­ modifying drugs that delay the underlying neurodegenerative process
cation of lipids, proteins, and carbohydrates. These aberrant processes (Kalia and Lang, 2015). The role of iron metabolism in PD offers new
can lead to various pathological changes, including neurodegenerative perspectives on PD drug development. In a study, researchers synthe­
diseases. In PD, loss of neurons is accompanied by altered cellular iron sized a novel 1-hydroxypyrazin-2(1 H)-one iron chelator and found it
distribution and accumulation, changes that can be recognized in MRI also delays the progression in vitro cell models of PD by prevening the
images of the SN, putamen, red nucleus, and globus pallidus (Ward generation of ROS (Lewis et al., 2022). While another iron chelator
et al., 2014). The structural spatial changes in the striatum show that deferiprone (DFP) can inhibit pathological toxicity of α-syn in a mouse
iron spatial variability increases with aging by the spatial variability of model of sporadic PD (Sterling et al., 2022). Brain imaging in PD pa­
two qMRI parameters (R2 * and MTV, which have been linked to iron tients also showed dopaminergic dysfunction progressing with iron
concentration and non-water content) (Drori et al., 2022). Tissue atro­ accumulation and depigmentation (Depierreux et al., 2021). Based on
phy and iron content variation can be significant signatures of brain the positive treatment results from the PD model, drugs targeting iron
aging. Some studies also show that iron levels in the SN also are asso­ deposition have been tested in clinical trials. But the clinical efficacy of
ciated with PD symptoms such as motor disability (Martin-Bastida et al., using DFP to treat patients has been much lower than expected. So far,
2017a). Another study on the relationship between inflammatory three Phase II clinical trials of DFP have been published, and only one
markers and iron deposits in PD patients discovered that microglial cell small-scale trial observed significant improvement in PD motor symp­
density and iron accumulation were more pronounced in the SN in PD toms with DFP treatment. (Devos et al., 2014). However, the other two
patients with varying levels of α-syn deposits than in controls. In patients trials, including a 36-week trial with 372 participants, found that
with early PD, plasma ferritin concentration is associated with IL-6, an although DFP could reduce iron deposition in the SN, it accelerated the
inflammatory cytokine. In addition, the rate of plasma ferritin and iron progression of both motor and non-motor symptoms in PD patients.
deposit in multiple deep gray matter nuclei was negatively correlated (Devos et al., 2022; Martin-Bastida et al., 2017b).
with the severity and duration of PD (Martin-Bastida et al., 2021). Liu
et al. thought that nervous system inflammation is related to the iron 3.3. Lipid metabolism in ferroptosis and PD
deposition induced proinflammatory cytokine release from microglia
cells, and the treatment of various neurological diseases can be realized Abnormal lipid metabolism also is a common feature of ferroptosis
by inhibiting ferroptosis that occurs in microglia cells (Liu et al., 2022). and PD. The PUFA phospholipids are targets for lipid peroxidation, and
Systemic inflammation is closely related to iron metabolism and PD this oxidative damage to cell membranes can lead to ferroptosis. The
pathology. Analyses of iron levels by quantitative susceptibility mapping brain is the most oxygen-consuming tissue in the body, and it contains
in ventral SN show a relation to PD progression (Bergsland et al., 2019). up to 60% fat (Liu et al., 2020). While brain fat is rich in PUFAs and most
Cells have iron import, export, and storage mechanisms to inhibit the of these PUFAs are made up of AA and docosahexaenoic acid (DHA)
production of excess unbound iron in cells, which otherwise could lead (Larrieu and Layé, 2018). Thus brain tissue may be more susceptible to
to the production of ROS. In this mechanism, iron in the blood is bound oxidation damages. SNpc neuronal death is a key pathological feature of
to Tf for transport and its import is mediated by DMT1 and TfR, and its PD, and one of the causes of this neuronal death is lipid peroxidation (Jin
export is mediated by FPN-1 (Ma et al., 2021). Many PD patients are et al., 2011). During the process of ferroptosis, a large number of free
found to have dysregulated expression of iron regulatory proteins radicals are generated, which can damage the phospholipid structure of

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the cell membrane bilayer. Neurons that suffer from this kind of damage Nowadays, more and more studies show that lipid metabolism plays
will decrease the activity of membrane-bound enzymes and will have an important role in the pathology of PD, and some argue that it is a
altered membrane permeability, factors that ultimately can lead to cell lipid-induced protein disease in which metabolic processes of lipid
death. In addition, the peroxidation of PUFAs in the cell membrane leads components can induce changes in proteins, such as the accumulation of
to the formation of aldehydes, one of the most of which is 4-hydroxy-2-­ α-syn, and lead to the loss of dopaminergic neurons and gradually lead
nonenal (HNE) (Di Domenico et al., 2017). The toxicity of HNE is mainly to the degeneration process (Fais et al., 2021). Similarly, altered lipid
due to the formation of covalent adducts with proteins and these cova­ metabolism is also the main promoter of ferroptosis. A series of enzymes
lent adducts alter cellular function (Romano et al., 2017). HNE is a toxic regulating lipid synthesis, storage, and degradation can enhance cells’
product resulting from lipid peroxidation. In the SN of PD brains, sensitivity to ferroptosis in abnormal lipid metabolism and finally
decreased GSH levels may be a crucial factor that contributes to eleva­ generate lethal lipid peroxides.
tion of HNE(Sofic et al., 1992). High levels of HNE change the trans­
portation pathway of dopamine and cause dopamine loss. Other studies 3.4. Other mechanisms linked to ferroptosis and PD
showed that HNE-related proteins are elevated in Lewy bodies of the SN
in PD and in the brainstem in Lewy body disease (Castellani et al., 2002; Microglia are a crucial factor in brain development and regulate the
Fabelo et al., 2011). Moreover, increased levels of HNE also were aging and degeneration processes (Silvin et al., 2022). These functions
observed in the cerebrospinal fluid of PD patients (Selley, 1998). Di link microglia to some neurological and psychiatric disorders. P2RY12 is
Domenico et al. performed a redox proteomics analysis and found one of the P2Y metabotropic G-protein-coupled purinergic receptors.
widely increased HNE-protein adduct formation in lines of C. elegans Compared with other brain and myeloid cell types, P2RY12 is highly
containing Leucine-rich repeat kinase 2 (LRRK2) and tau transgenic expressed in microglia and closely related to microglia migration and
forms (Di Domenico et al., 2017). There are direct or indirect in­ activation (Badimon et al., 2020). A systemic analysis of the human
teractions between these proteins. The discovery of the proteins that microglial transcriptome suggested that P2RY12 may be a potential risk
HNE targets revealed that the co-expression of mutated LRRK2 and tau gene for PD (Lopes et al., 2022). As for ferroptosis, many pieces of evi­
resulted in the oxidative modification of proteins involved in energy dence indicate that aging may be the underlying clue that connects PD
metabolism and in proteolytic pathways, including autophagy, sup­ and ferroptosis. Heme oxygenase-1 (HO-1) is a kind of inducible enzyme
porting the hypothesis that the alteration of those pathways by HNE may that regulates oxidative stress and inflammation. It has been reported
contribute to the development of PD (Di Domenico et al., 2012). Re­ that the increase of HO-1 expression in human astrocytes can induce
searchers recognized elevated HNE-protein adducts as markers of per­ parkinsonian features, and this phenomenon is also linked with ferric
oxidation in the brain and in body fluids of subjects with PD. These iron deposit (Cressatti et al., 2019; Song et al., 2017). Cristina et al.
HNE-protein adducts are strongly associated with cognitive decline. found aged wild mice (15–18 months-old) have higher expression levels
Some studies have demonstrated that ferroptosis induces glial cell of microglial HO-1 and alteration of iron-related metabolism proteins
death (Friedrich et al., 2021). Oligodendrocytes have the highest levels compared with young mice (3–4 months-old). Meanwhile, inhibition of
of iron among cells in the CNS and rapid iron mobilization by ferritin HO-1 completely prevents these alterations (Fernández-Mendívil et al.,
leads to lipid peroxidation and oligodendrocyte death, which in turn 2021). This study indicates that the age-related increase in expression of
causes ferroptosis in dopaminergic neurons (Wang et al., 2022). Cyto­ HO-1 subsequently affects iron metabolism, oxidative stress, and
kines and ROS that accelerate the death of dopaminergic neurons are inflammation; which are features that ultimately induce ferroptosis.
mainly produced by microglia (Sharma and Nehru, 2016). Phorbol The potential involvement of PKC in initiating ferroptosis has been
myristate acetate (PMA) treatment can give rise to iron-dependent lipid identified. PKC activation can induce ferroptosis by activating the RAS-
peroxidation by inducing superoxide-mediated release of iron from MEK pathway on one hand and by inhibiting the Nrf2 pathway on the
ferritin (Yoshida et al., 1998). In addition, inducible nitric oxide syn­ other, thereby disturbing cellular iron homeostasis and instigating iron-
thase (iNOS) is significantly upregulated in microglia under the influ­ dependent cell death (Do Van et al., 2016; Wang et al., 2023). Lund
ence of inflammatory signals to reduce 15-LOX activity to inhibit human mesencephalic (LUHMES) cells are a kind of neural precursor
ferroptosis (Kapralov et al., 2020). Oligodendrocytes can produce cells that have an extremely high proportion for transformation to
myelin in neural tissues, and iron in oligodendrocytes is a cofactor for dopaminergic marker-expressing neurons. In the PD model constructed
myelin synthase (McTigue and Tripathi, 2008). The iron in oligoden­ by LUHMES cells, erastin-induced ferroptosis requires PKCα to activate
drocytes can trigger the formation of hydroxyl radicals through the mitogen-activated protein kinase kinase in a RAS-independent manner,
Fenton reaction and induce lipid peroxidation (Wang et al., 2022). which may be specific to neuronal cells (Do Van et al., 2016). Mean­
Alterations in the serum lipids, which participate in the metabolic while, another study found that PKCβII senses the initial lipid peroxi­
pathways regulated by PD risk genes, were observed between those with dation event and phosphorylates Thr328 of ACSL4, phosphorylated
and without PD (Galper et al., 2022). One perspective is that alteration ACSL4 in turn activates and promotes PUFA phosphatidic acid forma­
in lipid metabolism is a crucial factor that precedes the development of tion and causes subsequent cellular ferroptosis (Zhang et al., 2022b).
PD (Fais et al., 2021). Significant alterations in lipid metabolism have Additionally, in rhabdomyosarcoma (RMS) cells, the broad-spectrum
also been found in experimental models expressing different PD causa­ PKC inhibitor Bisindolylmaleimide I, as well as the PKCα- and β-selec­
tive or susceptibility genes. Glucocerebrosidase (GBA) is a gene associ­ tive inhibitor Gö6976, significantly reduced erastin-induced ferroptosis.
ated with lipid metabolism, with an approximately tripled risk of PD in Similarly, genetic knockdown of PKCα significantly protected RMS cells
carriers of mild GBA mutations (N370S) and a fifteen-fold higher risk in from erastin-induced ferroptosis (Dächert et al., 2020). Moreover, the
carriers of severe GBA mutations (L44P or 84GG) (Gan-Or et al., 2015; activation of the PKC pathway induced by psychological stress promotes
Sidransky et al., 2009). The LRRK2 gene is mutated gene in some cases of PD progression through triggering ferroptosis in dopaminergic neurons
sporadic and familial PD, and it has also been shown that LRRK2 has an (Lin et al., 2023). The above research findings suggest that PKC in­
important role in lipid metabolism and lipid signaling pathways, with hibitors may emerge as robust candidates for pharmacologically
significant alterations in the lipid profile of LRRK2 knockout mice modulating the ferroptotic signaling cascade. However, it’s noteworthy
(Boddu et al., 2015; Funayama et al., 2022). Mutations in synaptojanin1 that some studies have discovered that phosphorylation of PKC induced
(SYNJ1) have been shown in a recent study to be responsible for by γ-glutamylcysteine (γ-GC) can inhibit ferroptosis in a model of Ce­
early-onset atypical parkinsonism, and SYNJ1 appears to play a role in rebral Ischemia/Reperfusion Injury (Zhang et al., 2022c).
regulating vesicular transport by modulating phospholipid signaling
(Cao et al., 2017; Quadri et al., 2013). These observations demonstrate
that there are multiple genetic links to altered lipid metabolism in PD.

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4. The relationship between PD-related proteins and ferroptosis proposed recently. It believes that α-syn accumulation inhibits Nrf2
protein levels, reducing the expression of Nrf2 target genes AKR1C1 and
The deeper molecular mechanisms by which ferroptosis has an GCLM, and then increasing susceptibility to ferroptosis. This viewpoint
impact on PD remain unclear, but we summarize here the connection has been verified in some in vitro and in vivo models of PD (A et al.,
between several PD-related proteins and ferroptosis (Fig. 4). 2022). To summarize, ferroptosis is critical for gaining a comprehensive
understanding of the mechanisms by which α-syn causes neurological
4.1. α-syn damage in the brains of PD patients.

The protein α-syn aggregation is the core of PD pathogenesis. α-syn 4.2. Nrf2
contributes to vesicle trafficking, vesicle docking, priming vesicle
fusion, and neurotransmitter release (Jankovic and Tan, 2020). How­ Nrf2 maintains redox homeostasis by binding to antioxidant
ever, the abnormal aggregation of α-syn is associated with toxicity and response elements which are present in the promoter regions of most
links with mitochondrial dysfunction, thus contributing to neuronal genes encoding antioxidant enzymes. Nrf2 deficiency leads to reduced
death (Rocha et al., 2018). Increasingly, studies have shown that α-syn production of antioxidant enzymes, and low levels of antioxidant en­
also is involved in the regulation of iron and lipid metabolism. The zymes are found in PD (Niu et al., 2021). Nrf2 therefore is a potential
classical ferroptosis inhibition drugs including iron chelators and therapeutic target for PD. Nfr2 has been found to regulate ferroptosis in
D-PUFA could inhibit neuronal cell death induced by toxic α-syn olig­ many ways (Song and Long, 2020). Ferroptosis inducers can activate the
omers, suggesting a link between ferroptosis and α-syn toxicity (Ange­ SQSTM1/p62-Keap1-Nrf2-AKR1C (metal binding protein MT-1 G)
lova et al., 2020). Some researchers used two highly relevant human pathway, which promotes transcription of quinone oxidoreductase-1,
dopaminergic neuronal models to demonstrate that reduced accumula­ HO-1, and ferritin heavy chain-1, ultimately promoting the occurrence
tion of α-syn in dopaminergic neurons can prevent ferroptosis, and of ferroptosis (Sun et al., 2016). SLC7A11-mediated cystine uptake plays
elevated α-syn expression in neuronal precursor cells derived from pa­ a key role in inhibiting oxidizing reactions and maintaining cell survival
tients with SNCA triplication resulted in increased vulnerability to lipid under conditions of oxidative stress. In a study on the role of ATF3 in
peroxidation and iron toxicity (Mahoney-Sanchez et al., 2022). Ange­ gastric cancer, researchers found that the mechanism by which ATF3
lova et al. constructed human stem cell-derived models of synuclein­ increased the sensitivity of gastric cancer cells to cisplatin was through
opathy characterized by intracellular α-syn neuronal aggregates bound the induction of ferroptosis by restraining the Nrf2/Keap1/XCT pathway
to membranes, through which they found that aggregate-membrane (Fu et al., 2021). Nrf2 also can directly bind to the sequence of the
interactions can induce ferroptosis (Angelova et al., 2020). However, SLC7A11 subunit promoter, which leads to increased expression of
the mechanisms of the interaction between α-syn, ferroptosis, and PD SLC7A11 (Carpi-Santos and Calaza, 2018). Nrf2 can directly or indi­
pathology remain unknown. Nrf2-α-syn-ferroptosis axis is a perspective rectly regulate expression of GPX4. Genes involved in GSH syntheses,

Fig. 4. The relation between PD-related proteins and ferroptosis. Unactivated Nrf2 binds to Keap1 in the cytoplasm. Under the stimulation of oxidative stress and
other factors, Nrf2 is released and transferred to the nucleus to bind to ARE, then activate the transcription of downstream genes to release a series of Cytoprotective
factors. At the same time, Nrf2 and DJ-1 act together to produce antioxidant factor MTs in reactive astrocyte, which import to neurons to fight against oxidative
stress. DJ-1 and Cytoprotective factors can also promote the GPX4 level. PARK2 gene expression product Parkin, together with DJ-1 and PINK1, promotes mitophagy
and eliminates defective or redundancy mitochondria, which are the main resources of ROS. Decreased ROS production indirectly inhibited α-syn production.

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such as SLC7A11, GSS, and GPX4, as well as redox enzymes that use GSH between PINK1 and ferroptosis may be complex, and requires additional
and NADPH to reduce oxidized substrates, such as GSH-S-transferases p1 studies.
(GSTP1) and α1 (GSTA1), peroxidases 1 (PRDX1) and peroxidases 6
(PRDX6), and thioredoxin reductase (TXNRD1), all are targets of Nrf2 4.5. DJ-1
(Hayes and Dinkova-Kostova, 2014). Nrf2 also can be released by
reactive astrocytes as an antioxidant factor and regulate metallothionein Mutations in Daisuke-Junko-1 (DJ-1) gene are another cause of early-
(MT) secretion; both Nrf2 and MTs are key neuroprotective targets onset PD (Singleton et al., 2013). Inhibition of oxidative damage is the
involved in iron homeostasis and oxidative stress. Extracellular MTs most important PD-related function of DJ-1. the progressive and
secreted by astrocytes have free radical scavenging properties because age-dependent loss of DJ-1 in neurons can lead to oxidative stress, with a
they are rich in sulfhydryl groups, which protect dopaminergic neurons lack of an adequate antioxidant response (Andres-Mateos et al., 2007;
from quinone toxicity (Hayes and Dinkova-Kostova, 2014). This pro­ Taira et al., 2004). DJ-1 can also regulate mitochondrial function and
tective mechanism also has been linked to ferroptosis. Thus, Nrf2 is a key mitophagy like Parkin and PINK1 (Kalia and Lang, 2015). These features
regulator of ferroptosis pathology and also may be important in PD suggest that DJ-1 may be involved in ferroptosis. Cao et al. suggested
pathology. that DJ-1 determines the sensitivity of cancer cells to ferroptosis. They
established several stable DJ-1 knockdown cancer cell lines and found
4.3. Parkin that the S-adenosyl homocysteine hydrolase tetramer formation was
inhibited in DJ-1 deficiency cells, which makes cancer cells more sen­
Autosomal recessive mutations in the PARK2 gene leading to a sitive to ferroptosis (Cao et al., 2020). In another study, Jiang et al.
decrease in Parkin are the most common cause of early-onset PD found evidence that the C terminus of DJ-1 is crucial to inhibit ferrop­
(Madsen et al., 2021). Parkin is an E3 ubiquitin ligase that can generate tosis. They performed deletion mutations in HEK293T cells with
K48- and K63- linked ubiquitin chains, which modify many cytosolic Flag-tagged and Myc-tagged DJ-1 overexpression, and found that DJ-1
and outer mitochondrial membrane proteins. Parkin effectively reduces lacking the last three amino acids at the C terminus can no longer
the occurrence of ubiquitin-mediated misfolding or impaired protein inhibit erastin-triggered ferroptosis (Jiang et al., 2021a). Interestingly,
degradation and mitochondrial dysfunction (Pickrell and Youle, 2015). Chen et al. also found that DM10, which acts by covalent binding to
In a study aims at evaluating the relationship between blood-brain DJ-1, exhibited inhibition of erastin-based ferroptosis in the human
barrier(BBB) disorders and Alzheimer’s disease, researchers found that cancer cell line H1299 (Chen et al., 2021c). In a group of studies, Liao
Amyloid β1–40, one of the common soluble monomer subtypes of Am­ et al. respectively compared the effects of ferroptosis inhibitors and in­
yloid β, induces ferroptosis by cooperating with CD36 and Parkin and ducers on BeWo cells with different DJ-1 expression levels, and they
finally leading to disruption of the BBB (Liu et al., 2021). This study concluded that DJ-1 could mediate ferroptosis in trophoblast cells by
reveals a potential connection between Parkin and ferroptosis. Mean­ regulating the Nrf2/GPX4 signaling pathway (Liao et al., 2022).
while, mitochondrial dysfunction has been defined as an important Recently, Wang et al. performed a chemical proteomic analysis of
factor for ferroptosis (Battaglia et al., 2020). Mitophagy refers to the functional cysteines in the proteome during ferroptosis and identified
preferential degradation of dysfunctional mitochondria. Parkin is a key C106 (one of the cysteine residues of DJ-1) as a redox sensor to inhibit
regulator of mitophagy (Youle and Narendra, 2011). The ferroptosis. They suggested that the proteolytic function of the 20 S
voltage-dependent anion channel (VDAC) is an important protein link­ proteasome is regulated by the C106 amino acid of DJ-1 and that pro­
ing mitophagy and ferroptosis, and it serves as a docking site for mito­ teasome activity in turn affects the process of ferroptosis. In addition to
chondria to recruit Parkin to defective mitochondria to induce the reported interaction of DJ-1 with the 20 S proteasome and its
mitophagy (Sun et al., 2012). Su et al. found that GSK3B increased VDAC inherent redox-sensitive protease activity, their data revealed a novel
phosphorylation in a model of oxidant stress kidney injury, and then mechanism that C106 oxidation of DJ-1 establishes a unique link be­
induced ferroptosis (Su et al., 2022). Overall, Parkin and ferroptosis tween the 20 S proteasome and ferroptosis (Wang and Wang, 2022).
show interesting connections, but the role of Parkin-related regulation of This mechanism of DJ-1 suggests that DJ-1 may be a promising target for
ferroptosis in the pathogenesis of PD is not yet clear. the development of therapeutics for diseases associated with ferroptosis.
What’s more, DJ-1, PINK1, and Parkin also can regulate mitophagy and
4.4. PINK1 inhibit oxidative stress (Wang et al., 2022).

Compared with mutations in Parkin, mutations in PTEN-induced 5. PD animal models and ferroptosis
kinase 1 (PINK1) are a less common causes of autosomal recessive
forms of PD (Singleton et al., 2013). Both Parkin and PINK1 have a Ferroptosis and its related pathological characteristics have been
strong influence on mitochondrial health through their impact on observed in various animal models of PD, as summarized in Table 2. One
mitophagy (Anzell et al., 2018). The E3 ubiquitin ligase Parkin and the widely employed PD model involves MPTP administration in non-
serine threonine protein kinase PINK1 can collaborate to deal with human primates and mice. MPTP enters neurons via the dopamine
damaged mitochondria in the mitophagy process. Several studies have transporter, leading to mitochondrial dysfunction and affecting sulfatide
shown that PINK1 also can influence ferroptosis in certain conditions. In distribution, ultimately causing damage to oligodendrocytes (Kaya
a study of the impact of iron metabolism in polycystic ovary syndrome et al., 2023). In the context of ferroptosis, the esterification of PUFAs by
(PCOS), researchers observed that transferrin receptors (TFRC) activa­ ACSL4 is a pivotal step. Remarkably, ACSL4 levels are significantly
tion increased intracellular iron levels along with increased PINK1 elevated in the SN of both MPTP-induced PD mouse models and PD
protein expression, which ultimately mediated the release of ROS and patients. In ACSL4 knockdown MPTP mice, motor deficits, dopamine
induced lipid peroxidation, processes that promoted the ferroptosis of loss, and lipid ROS accumulation are mitigated (Tang et al., 2023).
KGN cells (Zhang et al., 2021a). STING1 is a promoter of autophago­ Notably, a study highlights the coexistence of ferroptosis and increased
some formation, which can promote MFN1/2-dependent mitochondrial iron levels in MPTP models, with the latter being crucial in dopami­
fusion and promote erastin-induced ferroptosis (Gui et al., 2019; Li et al., nergic neuron degeneration (Li et al., 2023b).
2021). PINK1 is also a key regulator of mitochondrial autophagy in In another PD model utilizing 6-OHDA, which enters neurons via
mammalian cells (Li et al., 2021). However, a study found that although dopamine and noradrenaline transporters, oxidative stress is induced,
PINK1 is related to the functions of STING1, knockdown of PINK1 does triggering astrocyte and microglia activation and mitochondrial damage
not affect erastin-induced cell death in vitro or in xenograft mouse through radical generation or respiratory chain inhibition (Dovonou
models (Li et al., 2021). This result indicates that the relationship et al., 2023). Tian et al. reported a significant decrease in FTH1 levels in

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Table 2
Ferroptosis and pathogenic evidence in PD animal models.
Model Species α-synucleinopathy Dopamine Iron Ferroptosis Limitation
loss overload

Neurotoxic MPTP Rodents and Yes Yes Yes Yes Rodent models have no motor dysregulations
models primates and are highly variable.
6-OHDA Rodents, No Yes NR Yes 6-OHDA can not cross the BBB and induce α-syn
primates, and (Rodents) aggregation.
C. elegans
LPS Rodents Yes Yes Yes Yes LPS models have variable phenotype and low
specificity for PD.
Rotenone Rodents, Yes Yes Yes Yes Rotenone is toxic to other organs and causes
Drosophila, and (Rodents) (Rodents) non-specific brain damage.It also has variable
C. elegans phenotype and high mortality.
Paraquat Rodents, Yes Yes Yes Yes Paraquat is toxic to other organs and has low
Drosophila, and (Rodents) (Rodents) construct validity.
C. elegans
Genetic LRRK2 Mice Yes Yes Yes NR Lack of substantial DA neurodegeneration.
models
C. elegans NA Yes NR NR Lack of α-syn pathology.
Drosophila NA Yes NR NR Lack of α-syn pathology.
PINK1&PRKN Mice No Yes NR NR Neurodegeneration progresses slowly.
Primates NR Yes NR NR The phenotype develops too slowly and the cost
of model construction is high.
C. elegans NA Yes NR NR Lack of α-syn pathology.
Drosophila NA Yes Yes NR PRKN ortholog-deficient Drosophila have no DA
neuron loss.Lack of α-syn pathology.
GBA1 Mice Yes Yes NR NR GBA1 L444P heterozygous mice have no α-syn
aggregation.
Drosophila NA Yes NR NR Lack of α-syn pathology.
Foxa1/2 Mice No Yes NR NR Models should be constructed in mature mice.
Otx2 Mice NA Yes NR NR Models should be constructed in mature mice.
UCH-L1 Mice No Yes NR NR PD pathology appears late.
Drosophila NA Yes NR NR Lack of α-synu pathology.
DJ-1 Mice No Yes NR NR PD pathology appears late and slightly.Lack of
α-syn pathology.
Lmx1a/b Mice Yes Yes NR NR Models should be constructed in mature mice.
Pitx3 Mice NA Yes NR NR Models should be constructed in mature mice.
c-Rel Mice NA Yes Yes NR Models should be constructed in mature mice.
A30P human α-syn Mice Yes NR Yes NR DA neurons in SNpc have no degeneration.
C. elegans, Yes Yes Yes NR Low α-syn accumulation.
Drosophila (Drosophila)
A53T human α-syn Mice Yes NR Yes Yes α-syn inclusions are formed in non-PD-related
areas.
C. elegans, Yes Yes Yes NR No endogenous α-syn accumulation.
Drosophila (Drosophila)
E46K human α-syn Mice Yes NR Yes NR DA neurons in SNpc have no α-syn inclusions.
WT α-syn Mice Yes Yes Yes NR Degeneration of DA neurons in the SNpc has not
been reported.
C-terminally Mice Yes Yes NR NR α-syn expression is limited to DA neurons.
truncated α-syn
Others α-syn preformed Mice Yes Yes No No PD pathology appears late in WT mice.
fbrils
Primates Yes Yes NR NR The features of PD-derived pathological α-syn
can not be fully mimicked by recombinant
synthetic α-syn fibrils.
Neuromelanin-like Rodents Yes Yes Yes NR Unknown factors accelerate DA degeneration in
production the model.

NA: Not applicable; NR: Not reported

the 6-OHDA rat model, resulting in increased LIP levels, mitochondrial mitochondrial changes suggestive of ferroptosis, accompanied by iron
damage, and eventual ferroptosis (Tian et al., 2020). accumulation in the SN (Hu et al., 2023). Likewise, PD mouse models
Lipopolysaccharide (LPS) exposure activates inflammation and pro­ induced by paraquat present ferroptosis and iron overload (Zuo et al.,
motes α-syn deposition in idiopathic PD, particularly in a mitochondria- 2021).
dependent manner (Esteves et al., 2023). Although LPS-induced models Genetic factors also contribute to PD cases, with genes like LRRK2,
exhibit dopaminergic neuron loss, motor deficits, and neuro­ PINK1, PRKN, GBA1, Foxa1/2, DJ-1, and UCH-L1 recognized as poten­
inflammation, their specificity for PD is limited due to features over­ tial risk factors. In G2019S LRRK2 knock-in mouse models, along with
lapping with Alzheimer’s disease, such as tau protein phosphorylation typical PD features, increased iron accumulation within microglia in the
and memory loss (Wang et al., 2018). Additionally, iron overload has striatum has been noted (Mamais et al., 2021). Similarly, iron overload
been identified in the midbrain tissue of LPS-induced rat models, while is observed in various models involving PINK1, c-Rel, A30P, and E46K,
ferroptosis in LPS-induced mouse models was reported in an Alzheimer’s underlining its significance (Baiguera et al., 2012; Ohiomokhare et al.,
disease treatment study (Li et al., 2023c; Sharma and Nehru, 2018). 2020; Ostrerova-Golts et al., 2000; Ruf et al., 2019; Zhu et al., 2016).
PD models constructed with rotenone and paraquat also display signs Zhang et al. conducted experiments treating dopaminergic neurons with
of ferroptosis and iron overload. Rotenone-induced rat models exhibit ferric ammonium citrate (FAC) to simulate iron overload. The outcome,

10
X.-s. Ding et al. Ageing Research Reviews 91 (2023) 102077

whether ferroptosis or apoptosis, depended on FAC concentration, with

lower concentrations promoting ferroptosis and higher concentrations

(Boldyrev et al., 2008)

(Mischley et al., 2017)

(Martin-Bastida et al.,
(Holmay et al., 2013)

(Hashim et al., 2014)

(Hauser et al., 2009)

inducing apoptosis. In A53T mouse models, ferroptosis preceded

(Shults et al., 2002)

(Devos et al., 2014)

(Devos et al., 2022)

(Monti et al., 2019)

(Evans et al., 2019)

(Coles et al., 2018)

(Taghizadeh et al.,

(Beal et al., 2014)

apoptosis in the PD pathological process, underscoring the interplay
between ferroptosis, apoptosis, and iron overload (Zhang et al., 2020).

References
Iron’s role in α-syn aggregation has been demonstrated in vitro,

2017b)
2017)
while in α-syn preformed fibrils (PFFs)-injected mouse models, iron
enrichment inhibits α-syn pathology and its spread to specific brain re­
gions (Dauer Née Joppe et al., 2021; Davies et al., 2011). However,

Dopamine transporter binding was significantly increased in the caudate and putamen. PD

No significant increase in MDA, 4-HNE, or brain GSH. GSH/GSSH and blood catalase were
Iron content reductions in SN occurred in 3/14 patients. No significant improvement in
another study contradicts the involvement of ferroptosis in α-syn’s toxic

No significant difference between the GSH treatment group and the placebo group in
effects (Guiney et al., 2020). These intriguing findings warrant further

GSH increased and symptoms improved. Total antioxidant capacity also increased.
investigation into iron’s intricate role in α-syn-related PD pathology.

Superoxide dismutase (SOD) levels increased and motor symptoms improved.

Iron deposit reduced in SN and motor handicap improved in PD patients.
6. Ferroptosis clinical trials in PD patients cohort

Less iron content in SN but symptoms worse after 36 weeks treatment.

CoQ10 was well tolerated, but showed no evidence of clinical benefit.

Possibly beneficial, and the high dose of CoQ10 was well tolerated.
Increasing evidence supports the important role of ferroptosis in PD
pathology, and related clinical trials have also been carried out

GSH redox ratios and brain GSH increased in PD patients.

L-dopa absorption increased and PD symptoms improved.

(Table 3). In a pilot, double-blind, placebo-controlled randomized

Motor symptoms were improved in the high-dose group.

clinical trial, Devos et al. reported that early-stage PD patients, treated

Disease severity decreased and life quality improved.

with iron chelator DFP (30 mg/kg/day) for 12 months, showed reduced
iron accumulation in SN and improved motor-UPDRS scores (Devos
et al., 2014). Another phase II clinical trial reported that DFP reduced

symptoms were significantly improved.

iron deposits in the SN of 3 PD patients among 14 PD patients cohort
though the motor symptoms improvement have no significant (Mar­
tin-Bastida et al., 2017b). However, a large phase II placebo-controlled
trial for DFP was carried out by Devos et al. recently, and surprisingly, it
showed that DFP treated patients had worse symptoms than those on

significantly increased.
placebo after 36 weeks, although iron content was reduced in the SN
(Devos et al., 2022). N-acetyl cysteine (NAC) also may target ferroptosis

motor function.
and is being studied in PD clinical trials with potentially promising re­

symptoms.
sults (Coles et al., 2018; Holmay et al., 2013; Monti et al., 2019; Monti
Results

et al., 2016). The effect of CoQ10 also has been investigated, with an
initial study suggesting potential benefit (Shults et al., 2002), but a
subsequent phase 3 study in 600 early PD patients showed no clinical
benefits (Beal et al., 2014; Seet et al., 2014; Shults et al., 2002). Simi­
larly, GSH also showed different treatment effects in two clinical studies;
Mischley et al. observed motor improvements in the high dose group Helicobacter pylori inhibition or lipid
whereas Hauser et al. observed no improvements with GSH compared to
Radical-trapping antioxidants

Lipid peroxidation inhibition

Lipid peroxidation inhibition
placebo (Hauser et al., 2009; Mischley et al., 2017). Treatment with
Antioxidant, GSH precursor
Antioxidant, GSH precursor

Antioxidant, GSH precursor

Drug action mechanisms

omega-3 fatty acids and vitamin E led to symptom improvement and

peroxidation inhibition

increased GSH concentrations in a Phase II randomized controlled trial

(Taghizadeh et al., 2017). Carnosine, an endogenous histidyl dipeptide,
acts to conjugate lipid peroxides, providing oxidation protection (Zhao
Iron chelator

Iron chelator

Iron chelator
Antioxidant
Antioxidant

Antioxidant
Antioxidant
et al., 2019). Carnosine supplementation has shown potential symp­
tomatic beneifts in a clinical trial in PD (Boldyrev et al., 2008).
CuII(atsm) has been found to reduce iron overload-induced lipid per­
oxidation and to prevent cell ferroptosis. A CuII(atsm) phase II clinical
trial showed that the disease severity of PD patients decreased after
ω3 Fatty acids and

CuII(atsm) treatment (Evans et al., 2019). Interestingly, a clinical trial in

2014 showed that eliminating Helicobacter pylori by omeprazole can
Ferroptosis related clinical trials in PD patients cohort.

Omeprazole

CuII(atsm)

promote the absorption of acute L-DOPA in PD patients and then

Carnosine
vitamin E
CoQ10

CoQ10
Agents

improve motor severity and quality of life parameters (Hashim et al.,

NAC
NAC

NAC
GSH

GSH
DFP

DFP

DFP

2014). However, a recent study reported that omeprazole was also a

ferroptosis inhibitor, which could inhibit lipid peroxidation (Mishima
IRCT201604035623N73
IRCT201604035623N73

et al., 2020). Therefore, the deeper mechanisms of omeprazole in the

treatment of PD remain to be further explored.
Identifier number

NCT00943748
NCT01427517
NCT02445651

NCT00004731
NCT02424708

NCT02112812

NCT01539837

NCT02655315
NCT02212678

NCT00740714
NCT02424708

7. Treatment strategies targeting ferroptosis in PD

7.1. Targeting iron accumulation regulators

Iron homeostasis impacts the vulnerability cells to ferroptosis.

Applicable

Applicable

Increasingly studies showed that targeted therapies for iron accumula­

Trial phase

Negative

Phase III
results

results

tion can significantly affect pathophysiological pathways of relevance to

Phase II
Phase II

Phase II

Phase II
Phase II

Phase II

Phase II
Phase II

Phase II
Phase II
Positive

Phase I
Table 3

PD. Clioquinol(CQ), an antiparasitic drug, was found that can regulate

Not

Not

iron homeostasis in tissues and inhibit ferroptosis (Li et al., 2022; Lv

11
X.-s. Ding et al. Ageing Research Reviews 91 (2023) 102077

et al., 2021). Shi et al. constructed a kind of monkey model of PD with vehicle-treated mice, Thy1-aSyn mice treated with 2.0 or 4.0 mg/d IN
stable symptoms and found that CQ could significantly alleviate both carnosine showed lower α-syn accumulation in the SNpc (Brown et al.,
dyskinesia and no-motor impairments in these models along with the 2021). Fer-1 is a recognized inhibitor of ferroptosis, which scavenges
reduction of iron accumulation and ROS levels in the SN (Shi et al., alkoxyl radicals, reduces unstable iron levels, and scavenges lipid per­
2020). Dexrazoxane(Dex) is an iron chelator, it uses a mechanism like oxides (Miotto et al., 2020). In various PD models in vitro and in vivo,
Fer-1 to prevent doxorubicin-induced ferroptosis (Fang et al., 2019). Mei fer-1 has led to significant improvements in PD-related motor behaviors
et al. found that Dex could not only cross the impaired blood-brain and pathological changes (Kabiraj et al., 2015). In the
barrier (BBB) but also could significantly improve contralateral rota­ unilaterally-lesioned 6-OHDA adult mouse model of PD and the 6-OHDA
tional behavior in 6-OHDA-induced models of PD and motor dysfunc­ induced cell model, Huang et al. found that fer-1 can inhibit the decrease
tions in MPTP-induced models of PD (Mei et al., 2019). Zinc of GPX4 and the increase of Sorting Nexin 5 (SNX5) so it was able to
protoporphyrin 9 (ZnPP) attenuated ferroptosis and reduced intracel­ inhibit ferroptosis (Huang et al., 2022; Thiele et al., 2012). Bai et al.
lular iron accumulation by inhibiting heme oxygenase-1 (HO-1), which found that fer-1 attenuated MPP+ induced decreases in GPX4 and TRX-1
may reduce HO-1 induced neuroinflammatory iron accumulation during in PC 12 cells and SH-SY5Y cells, and they concluded that TRX-1 regu­
aging and age-related neurodegenerative diseases like PD (Fernández-­ lates GPX4 and GSH and may prevent ferroptosis in PD pathology (Bai
Mendívil et al., 2021; Li et al., 2020b). Meanwhile, another report found et al., 2021). Liproxstatin-1 (Lip-1) is a radical trapping antioxidant
that elevated HO-1 has a neuroprotective effect because ZnPP could (RTA). It can inhibit iron deposition and lipid peroxidation, which
exacerbate MPP+ or α-syn-induced oxidative damage in astrocytes and makes it an inhibitor of ferroptosis (Chen et al., 2021b; Lillo-Moya et al.,
neurons (Yu et al., 2016). Despite the fact that theoretical and preclin­ 2021). Guiney et al. found that Lip-1 could protect the viability of
ical data indicate that iron metabolism targeting therapies are promising striatal neuron-derived and dopaminergic neuron-derived cell lines
in the treatment of PD, the most recent large-scale clinical trial found which have been exposed to PFFs (Guiney et al., 2020). Interestingly,
that DFP was associated with worse outcomes rather than benefits Lip-1 was used as a control in another experiment that aimed to evaluate
(Devos et al., 2022). The poor outcomes observed in clinical trials of iron the ability of CuII (atsm) to suppress ferroptosis. CuII (atsm) has been
chelation therapies targeting iron metabolism can potentially be shown to protect against neurodegeneration, and also showed inhibitory
attributed to two main factors. Firstly, iron chelators like DFP can inhibit effects on lipid peroxidation and ferroptosis in neuronal cell models of
the rate-limiting enzyme, tyrosine hydroxylase, involved in dopamine ferroptosis induced by RSL3 and erastin (Southon et al., 2020). Another
synthesis, which operates in an iron-dependent manner. Secondly, the study compared indicators of immune-inflammatory stress and reactive
patients enrolled in the clinical trial did not receive L-DOPA treatment, a oxygen and nitrogen species in healthy individuals and PD patients, and
departure from previous iron chelation trials. This absence of L-DOPA found that LOOH, malondialdehyde (MDA), and superoxide dismutase
treatment might have exacerbated the dopamine deficiency caused by are associated with PD progression. They suggested that lipid peroxi­
iron chelators. However, it’s worth noting that patients treated with iron dation could be another drug target (de Farias et al., 2016). Oxidative
chelation did demonstrate improvements in brain volume compared to damage and repair of unsaturated fatty acid chains of phospholipids in
the control group. Therefore, a novel approach could involve combining biofilms often occur simultaneously, but if not promptly repaired will
iron chelation with L-DOPA in future clinical trials. induce accumulation of phospholipid peroxide and ferroptosis (Jiang
et al., 2021b; Tang et al., 2021). The Ca2+-independent phospholipase
7.2. Targeting lipid peroxidation regulators A2β (iPLA2β, PLA2G6, or PNPLA9 gene) plays an important role in
oxidative phospholipid repair and clinical studies have shown that
CoQ10 works as a lipid-soluble antioxidant, performing important PNPLA9 mutations are associated with an increased risk of PD (Houlden
roles in the metabolism of fatty acids, pyrimidines, and lysosomes, as and Singleton, 2012; Lin et al., 2018; Sun et al., 2021). Based on the
well as regulating the expression of several genes that are involved in accumulation of oxidized phospholipids in PD cells with an iPLA2β
cell signaling, metabolism, transcriptional regulation, and oxidative mutation, researchers have extracted phospholipids from healthy
phosphorylation (Hargreaves et al., 2020). CoQ10 and its reduced form human cells H109 and PD cells with an iPLA2β mutation, conducted
CoQ10-H2 can effectively inhibit ferroptosis and also acts as an antiox­ omics experiments, and assessed their vulnerability to ferroptosis. The
idant for mitochondrial and lipid ROS (Stockwell et al., 2017). CoQ10 results indicate that iPLA2β is an important regulator of ferroptosis. The
metabolism may be related to PD. The pathogenesis of PD is related to accumulation of lipid peroxides in the brains of PD patients caused by
neuroinflammatory production and excessive production of free radicals the inactivation of iPLA2β is closely related to the occurrence of PD, and
(Testai et al., 2021). CoQ10 is an antioxidant with anti-inflammatory inhibition of ferroptosis is predicted to be an effective treatment strategy
properties, so it was teseted as a therapeutic strategy for PD in recent (Sun et al., 2021).
years (Gutierrez-Mariscal et al., 2019). Meanwhile, CoQ10 level is
observed lower in PD patients when compared with normal people 7.3. Other regulators
(Leathem et al., 2022). A meta-analysis showed that compared to the
control group, PD patients had decreased levels of CoQ10 in the cere­ Apolipoprotein E receptor-2 (apoER2) is a member of the low-
bellar cortex, platelets, and lymphocytes, increased levels of total and density lipoprotein receptor family. It is predominantly expressed in
oxidized CoQ10 in the cerebrospinal fluid and a non-significant trend of the brain and testes. The interaction of apoER2 with selenoprotein P
decreased serum/plasma CoQ10 levels (Jiménez-Jiménez et al., 2022). maintains selenium levels at a homeostatic level in the mouse brain and
However, a large phase III placebo-controlled study of CoQ10 that prevents selenium deficiency-induced neurological impairment under a
showed no benefits on slowing progression. One perspective is that low-selenium diet (Burk et al., 2007). A familial Alzheimer’s disease
mitochondrial oxidative damage is a result of other pathological pro­ study showed that selenium was dramatically reduced in the brains of
cesses rather than the cause of neurodegeneration. Therefore, targeting apoER2 knockout mouse, leading to functional impairment of the
this pathway is not expected to provide benefits for PD. CoQ10 has checkpoint protection by the selenoprotein GPX4 (Greenough et al.,
shown neuroprotective activity in a variety of preclinical disease 2022). The two studies suggest an important link between selenium and
models, including cell cultures and animal models of PD and other ferroptosis in neurons. Aliem et al. observed that selenium can protect
neurodegenerative diseases, but its actual clinical value remains to be neurons by activating the transcription factors TFAP2c and Sp1. They
discussed (Beal et al., 2014). Carnosine can act to bind lipid peroxides, thought that this protective mechanism occurs because selenium in­
protecting against oxidative damage (Zhao et al., 2019). Brown et al. hibits processes such as ferroptosis, endoplasmic reticulum stress, and
gave intranasal (IN) carnosine (0.0, 2.0, or 4.0 mg/day) to wild-type and excitotoxicity in neurons (Alim et al., 2019). What’s more, clinical
Thy1-aSyn transgenic mice and found that compared with studies have confirmed that selenium concentrations are significantly

12
X.-s. Ding et al. Ageing Research Reviews 91 (2023) 102077

reduced in the serum of PD patients, and selenoprotein dysfunction has accumulation (Li et al., 2023b). Similarly, α-lipoic acid (ALA) enhances
been observed in PD patients (Jiménez-Jiménez et al., 1995; Zhang antioxidant defenses, regulates iron metabolism, and suppresses
et al., 2019). Recently, selenium has been found to increase selenopro­ iron-dependent ferroptosis, ameliorating PD symptoms (Zheng et al.,
tein expression, alleviate α-syn accumulation in the brain, and amelio­ 2023). In erastin-induced ferroptosis, Dl-3-n-butylphthalide (NBP) in­
rate PD-induced motor deficits in 6-OHDA models of PD. The results of creases FTH1 through Nrf2, preventing iron-dependent ferroptosis by
this experiment support the possibility of selenium therapy for PD averting iron autophagy (Ye et al., 2023). Rapamycin inhibits
(Salaramoli et al., 2023). However, overexposure to selenium was iron-dependent ferroptosis by activating cellular autophagy, thereby
regarded as a risk factor for PD in the cerebrospinal fluid in a improving PD features (Liu et al., 2023). Minocycline, a tetracycline,
meta-analysis, so the selenium neurotoxicity should be considered in the lowers ROS in neurons, protecting against iron-mediated oxidative stress
development of anti-PD drugs targeting selenium drugs (Adani et al., and ferroptosis (Tourville et al., 2023). Activation of the δ-opioid re­
2020). NAC is a promising ferroptosis inhibitor, and it has multiple ceptor stimulates Nrf2, suppressing iron-dependent ferroptosis, showing
mechanisms to prevent oxidative damage and ferroptotic cell death. In potential neuroprotection (Cai et al., 2023). Beta-hydroxybutyrate
addition to directly involved in the GSH biosynthesis, NAC can interact (BHB) reduces lipid peroxidation by downregulating ACSL4 through
with radicals and promote the restoration of damaged targets. It neu­ zinc finger protein36, mitigating ferroptosis in a PD model (Yu et al.,
tralizes the toxic lipids produced by ALOX5 and cooperates with 2023). The drug Lapatinib (LAP) enhances antioxidative capacity, in­
GSH-dependent enzymes to suppress reactive lipids (Karuppagounder hibits ACSL4, and activates the Nrf2 pathway, reducing iron-dependent
et al., 2018). Ezerina et al. suggested that sulfane sulfur is the actual ferroptosis and improving PD symptoms (Mansour et al., 2023). The
substance responsible for the antioxidant and cellular protective effects probiotic L. lactis MG1363-pMG36e-GLP-1 boosts antioxidative de­
of NAC. NAC is desulfurated to hydrogen sulfide and subsequently fenses, curbing iron-dependent ferroptosis, leading to dopamine neuron
oxidized to sulfane sulfur species (e.g. hydropersulfides) under the effect protection, enhanced barrier integrity, and microbial balance (Yue et al.,
of 3-mercaptopyruvate sulfurtransferase and sulfide:quinone oxidore­ 2022). Clausenamide, a lipid peroxidation scavenger, prevents
ductase in mitochondria (Ezeriņa et al., 2018). Recently, a study sug­ ALOX5-mediated ferroptosis, showing potential in neuroprotection (Li
gested that hydropersulfides were increased in ferroptosis cells to form et al., 2023a).
an adaptive cellular response. Cystine could also produce hydro­
persulfide, which terminates the radical chain reactions and inhibits 8.2. Advances in the epigenetics of ferroptosis
ferroptotic cell death in a GPX4-independent manner (Barayeu et al.,
2023). Due to its antioxidant and neuroprotective effects in the brain, The impact of epigenetic regulatory mechanisms on neuronal fer­
NAC is also considered to have a potential regulatory role in the path­ roptosis remains unclear. Recent investigations have unveiled that
ological progression of PD and applied to clinic trial. In a randomized hemin-induced ferroptosis coincides with an elevation in the global level
controlled trial, 42 PD patients were randomized to intravenous NAC of trimethylation at histone 3 lysine 9 (H3K9me3) and its methyl­
(50 mg/kg) or oral NAC (500 mg twice per day) while continuing their transferase Suv39h1. This H3K9 trimethylation regulates neuronal fer­
current treatment, an increase in dopamine transporters in the caudate roptosis by repressing Tfr1. Insights from this study enhance our
and putamen was observed after three months in patients treated with understanding of epigenetic regulation in neuronal ferroptosis (Lan
NAC compared with patients without NAC treatment (Monti et al., et al., 2023a). The condition of ferroptosis, triggered by CoQ10 down­
2019). The modes of intake of NAC are also related to its influence on regulation and the activation of non-coding microRNAs, is closely linked
PD. High intravenous doses of NAC significantly increases blood GSH to the accumulation of free radicals, cancer, and neurodegenerative
levels in PD patients and healthy controls, whereas another controlled diseases (Prasad Panda and Kesharwani, 2023). A recent bioinformatic
clinical trial failed to observe an increase in GSH in the presence of some analysis of target genes and miRNA-gene interaction networks has
dose oral NAC (Brunswick et al., 2003; Coles et al., 2018; Monti et al., identified hsa-mir-34a-5p and has-mir-106b-5p as regulators of both
2016). In the last 10 years, both clinical trials and in vitro models have CYBB and ACSL4 expression, thus influencing ferroptosis (Tian et al.,
shown that NAC has a significant effect against PD pathology, and some 2023). Numerous epigenetic drugs targeting ferroptosis have shown
studies considered the combination of NAC and L-DOPA as a new di­ efficacy in fields like cancer and cardiovascular diseases. Therefore,
rection for PD treatment in the future (Martínez-Banaclocha, 2012). modifying the ferroptosis pathway through drugs targeting epigenetic
Dynasore, another ferroptosis inhibitor that blocks ferroptosis by regu­ processes could present a new avenue for PD treatment (Lan et al.,
lating iron metabolism and inhibiting mitochondrial respiration, is more 2023b).
effective at blocking ferroptosis than NAC (Clemente et al., 2020). Chen
et al. reported that dynasore affected autophagy and disease-related 8.3. The role and significance of glial cells in neuronal ferroptosis
protein accumulation by the mTORC1-TFEB signaling pathway in
neurodegenerative diseases (Chen et al., 2019). Dopamine also regulates The recently discovered gene SEC24B plays a vital role in regulating
ferroptosis. Wang et al. reported that dopamine could inhibit ferroptosis. Researchers used a tri-culture system derived from plurip­
erastin-induced ferroptosis in cancer and non-cancer cells (Wang et al., otent stem cells, comprising neurons, astrocytes, and microglia. When
2016). However, a recent study found that dopamine acts on the pro­ exposed to iron and the ferroptosis inducer RSL3, microglia in the tri-
neural (PN) GBM stem cells (GSCs), which induces higher TF receptor 1 culture system showed the highest transcriptional activity and accu­
expression in mesenchymal (MES) GSCs, changes that promote iron mulated the most iron. Interestingly, removing microglia led to delayed
uptake and increased ferroptosis vulnerability (Vo et al., 2022). Thus, and reduced iron-mediated neuronal cell death. Microglia were identi­
the potential relationship between dopamine deficiency in PD and the fied as key drivers of iron-dependent neurodegeneration, with SEC24B
impact of dopaminergic treatments on ferroptosis is uncertain and identified through a genome-wide CRISPR screen as a critical regulator
complex. of microglial-mediated ferroptosis. SEC24B encodes a COPII vesicle
protein that affects iron homeostasis by influencing iron transport pro­
8. Novel insights from 2023 teins (Ryan et al., 2023).
Additionally, the autism-associated gene Cntnap4 may impact the
8.1. Targeting ferroptosis for dopaminergic neuron protection disease through microglia. A53T mice lacking Cntnap4 exhibited
compromised mitochondria in dopaminergic neurons, iron-induced cell
In the MPTP mouse model, the neuroprotective agent morroniside death, and increased α-synuclein release. Depletion or antagonism of the
improves motor deficits and boosts dopamine synthesis by activating the C3a receptor on microglia improved these effects. This implies that
Nrf2/ARE pathway, enhancing antioxidant capacity, and curbing iron Cntnap4 expression might inhibit the jointly-driven inflammatory

13
X.-s. Ding et al. Ageing Research Reviews 91 (2023) 102077

response of microglia and astrocytes, triggered by dopaminergic neuron Anzell, A.R., Maizy, R., Przyklenk, K., Sanderson, T.H., 2018. Mitochondrial quality
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dopaminergic neuron loss, and other features of Parkinson’s disease Asci, R., Vallefuoco, F., Andolfo, I., Bruno, M., De Falco, L., Iolascon, A., 2013. Trasferrin
(Zhang et al., 2023). receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP⁺ as
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Badimon, A., Strasburger, H.J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P.,
9. Conclusion Chan, A.T., Graves, S.M., Uweru, J.O., Ledderose, C., Kutlu, M.G., Wheeler, M.A.,
Kahan, A., Ishikawa, M., Wang, Y.C., Loh, Y.E., Jiang, J.X., Surmeier, D.J., Robson, S.
C., Junger, W.G., Sebra, R., Calipari, E.S., Kenny, P.J., Eyo, U.B., Colonna, M.,
While the exact mechanisms underlying PD pathogenesis are still not Quintana, F.J., Wake, H., Gradinaru, V., Schaefer, A., 2020. Negative feedback
fully understood, evidence suggests that various risk factors, including control of neuronal activity by microglia. Nature 586, 417–423.
iron accumulation, lipid peroxidation, oxidative stress, and aging, Bai, L., Yan, F., Deng, R., Gu, R., Zhang, X., Bai, J., 2021. Thioredoxin-1 rescues MPP(+)/
MPTP-induced ferroptosis by increasing glutathione peroxidase 4. Mol. Neurobiol.
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dependent form of regulated cell death, has recently been implicated Baiguera, C., Alghisi, M., Pinna, A., Bellucci, A., De Luca, M.A., Frau, L., Morelli, M.,
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turn activate ferroptotic pathways. Additionally, dopamine loss, which Issels, R.D., Daniel, P.T., Conrad, M., Bornkamm, G.W., 2008. The cystine/cysteine
cycle: a redox cycle regulating susceptibility versus resistance to cell death.
is a hallmark of PD, may increase susceptibility to ferroptotic cell death.
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Several other factors, including oxidative stress, iron accumulation, and Barayeu, U., Schilling, D., Eid, M., Xavier da Silva, T.N., Schlicker, L., Mitreska, N.,
aging, also contribute to the ferroptotic death of dopaminergic neurons Zapp, C., Gräter, F., Miller, A.K., Kappl, R., Schulze, A., Friedmann Angeli, J.P.,
Dick, T.P., 2023. Hydropersulfides inhibit lipid peroxidation and ferroptosis by
in PD. Given the role of ferroptosis in PD, targeting ferroptotic pathways
scavenging radicals. Nat. Chem. Biol. 19, 28–37.
represents a potential therapeutic strategy for the treatment of PD. Battaglia, A.M., Chirillo, R., Aversa, I., Sacco, A., Costanzo, F., Biamonte, F., 2020.
Several ferroptosis regulators, including GPX4, ferroptosis suppressor Ferroptosis and cancer: mitochondria meet the "iron maiden" cell death. Cells 9.
protein 1 (FSP1), and iron chelators, have been shown to have neuro­ Beal, M.F., Oakes, D., Shoulson, I., Henchcliffe, C., Galpern, W.R., Haas, R., Juncos, J.L.,
Nutt, J.G., Voss, T.S., Ravina, B., Shults, C.M., Helles, K., Snively, V., Lew, M.F.,
protective effects in animal models of PD. Despite the fact that theo­ Griebner, B., Watts, A., Gao, S., Pourcher, E., Bond, L., Kompoliti, K., Agarwal, P.,
retical and preclinical data indicate that iron metabolism targeting Sia, C., Jog, M., Cole, L., Sultana, M., Kurlan, R., Richard, I., Deeley, C., Waters, C.H.,
therapies are promising in the treatment of PD, the most recent large- Figueroa, A., Arkun, A., Brodsky, M., Ondo, W.G., Hunter, C.B., Jimenez-Shahed, J.,
Palao, A., Miyasaki, J.M., So, J., Tetrud, J., Reys, L., Smith, K., Singer, C., Blenke, A.,
scale clinical trial found that DFP was associated with worse outcomes Russell, D.S., Cotto, C., Friedman, J.H., Lannon, M., Zhang, L., Drasby, E., Kumar, R.,
rather than benefits. This study result raises doubts about the promise of Subramanian, T., Ford, D.S., Grimes, D.A., Cote, D., Conway, J., Siderowf, A.D.,
directly targeting iron accumulation as a strategy to counteract ferrop­ Evatt, M.L., Sommerfeld, B., Lieberman, A.N., Okun, M.S., Rodriguez, R.L.,
Merritt, S., Swartz, C.L., Martin, W.R., King, P., Stover, N., Guthrie, S., Watts, R.L.,
tosis for PD. However, there remains the possibility that other strategies Ahmed, A., Fernandez, H.H., Winters, A., Mari, Z., Dawson, T.M., Dunlop, B.,
to target ferroptosis ultimately could prove useful. Feigin, A.S., Shannon, B., Nirenberg, M.J., Ogg, M., Ellias, S.A., Thomas, C.A.,
In conclusion, ferroptosis represents a novel and promising target for Frei, K., Bodis-Wollner, I., Glazman, S., Mayer, T., Hauser, R.A., Pahwa, R.,
Langhammer, A., Ranawaya, R., Derwent, L., Sethi, K.D., Farrow, B., Prakash, R.,
the development of new therapies for PD.
Litvan, I., Robinson, A., Sahay, A., Gartner, M., Hinson, V.K., Markind, S.,
Pelikan, M., Perlmutter, J.S., Hartlein, J., Molho, E., Evans, S., Adler, C.H., Duffy, A.,
Lind, M., Elmer, L., Davis, K., Spears, J., Wilson, S., Leehey, M.A., Hermanowicz, N.,
Funding
Niswonger, S., Shill, H.A., Obradov, S., Rajput, A., Cowper, M., Lessig, S., Song, D.,
Fontaine, D., Zadikoff, C., Williams, K., Blindauer, K.A., Bergholte, J., Propsom, C.S.,
This work was supported by National Natural Science Foundation of Stacy, M.A., Field, J., Mihaila, D., Chilton, M., Uc, E.Y., Sieren, J., Simon, D.K.,
China (Grant No. 81971186 and No. 82271453) (L.G.), Shaanxi Pro­ Kraics, L., Silver, A., Boyd, J.T., Hamill, R.W., Ingvoldstad, C., Young, J., Thomas, K.,
Kostyk, S.K., Wojcieszek, J., Pfeiffer, R.F., Panisset, M., Beland, M., Reich, S.G.,
vincial Association of Science and Technology Youth Talents Lifting Plan Cines, M., Zappala, N., Rivest, J., Zweig, R., Lumina, L.P., Hilliard, C.L., Grill, S.,
(Grant No. 20190302) (B.W.), Shaanxi Province Youth Science and Kellermann, M., Tuite, P., Rolandelli, S., Kang, U.J., Young, J., Rao, J., Cook, M.M.,
Technology Rising Star (2023KJXX-028) (B.W.) and Tangdu Hospital Severt, L., Boyar, K., 2014. A randomized clinical trial of high-dosage coenzyme Q10
in early Parkinson disease: no evidence of benefit. JAMA Neurol. 71, 543–552.
Youth Talent supporting Plan (No. 2023ATDQN004. B.W.). Beatty, A., Singh, T., Tyurina, Y.Y., Tyurin, V.A., Samovich, S., Nicolas, E., Maslar, K.,
Zhou, Y., Cai, K.Q., Tan, Y., Doll, S., Conrad, M., Subramanian, A., Bayır, H.,
Kagan, V.E., Rennefahrt, U., Peterson, J.R., 2021. Ferroptotic cell death triggered by
conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12, 2244.
Declaration of Competing Interest Belaidi, A.A., Gunn, A.P., Wong, B.X., Ayton, S., Appukuttan, A.T., Roberts, B.R., Duce, J.
A., Bush, A.I., 2018. Marked Age-Related Changes in Brain Iron Homeostasis in
The authors declare that they have no competing interests. Amyloid Protein Precursor Knockout Mice. Neurother.: J. Am. Soc. Exp. Neurother.
15, 1055–1062.
Belaidi, A.A., Masaldan, S., Southon, A., Kalinowski, P., Acevedo, K., Appukuttan, A.T.,
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