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REVIEW ARTICLE OPEN

The Hippo signalling pathway and its implications in human

health and diseases
Minyang Fu1, Yuan Hu2, Tianxia Lan1, Kun-Liang Guan3, Ting Luo1 ✉ and Min Luo 1✉

As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological
processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo
pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and
tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer,
eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore,
therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide
spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical
physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway
and potential therapies targeting Hippo components will be discussed.

Signal Transduction and Targeted Therapy (2022)7:376 ; https://doi.org/10.1038/s41392-022-01191-9

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INTRODUCTION In this review, key components, upstream signals of the Hippo

The Hippo pathway was first discovered in Drosophila melanoga- pathway, and critical physiological functions controlled by this
ster and has been studied for the past 20 years. A timeline of pathway will be discussed. In addition, studies focusing on the
essential discoveries and processes of the Hippo pathway is consequences of the dysregulated Hippo pathway and potential
shown in Fig. 1. In mammals, the Hippo pathway is composed of therapeutic strategies targeting Hippo components will be
several key components, including mammalian STE20-like kinase evaluated. Moreover, the outcomes of drugs that manipulate the
1/2 (MST1/2), protein Salvador homologue 1 (SAV1), MOBKL1A/B activity of the Hippo pathway will be analysed.
(MOB1A/B), large tumour suppressor kinase 1/2 (LATS1/2), Yes-
associated protein 1 (YAP), WW-domain-containing transcription Key components of the Hippo pathway
regulator 1 (TAZ), and the transcriptional enhanced associated The core of the Hippo pathway is a kinase cascade, and MST1/2,
domain (TEAD) family1 (Fig. 2). YAP/TAZ are transcriptional SAV1, LATS1/2, YAP, and TAZ are considered the key compo-
coactivators that bind to TEAD1–4 to regulate the expression of nents.20–22 In general, the striatin (STRN)-interacting phosphatase
a wide array of genes that mediate cell proliferation, apoptosis, and kinase (STRIPAK) complex works upstream of kinase kinase
and stem cell self-renewal.2 Moreover, a variety of upstream kinase kinases (MAP4Ks) and MST1/2 and inhibits the Hippo
signals, such as cell polarity, mechanical cues, cell density, soluble pathway.23–26 However, when the Hippo pathway is activated,
factors and stress signals, modulate the Hippo pathway.3–5 MAP4Ks, MST1/2 and its scaffold protein SAV1 phosphorylate
As a signalling pathway that modulates the proliferation, LATS1/2 and its scaffold MOB1A/B.27 Then, activated LATS1/2
differentiation, and survival of cells, the Hippo pathway plays vital phosphorylates and inhibits YAP and TAZ, preventing them from
role in the development and homoeostasis of organs. Therefore, translocating into the nucleus to interact with TEAD 1–4.28
dysregulation of the Hippo pathway can cause a variety of MST1 and MST2 are serine/threonine kinases whose activity can
diseases, including cancer,6,7 eye diseases,8,9 cardiac diseases,10,11 be enhanced by being complexed with the scaffold protein SAV1
pulmonary diseases,12,13 renal diseases,14,15 hepatic diseases,16,17 through their C-terminal SARAH (Sav/Rassf/Hpo) domains.29 MST1/
and immune dysfunction.18,19 Thus, developing therapeutic 2 also facilitates the binding between MOB1A/B and LATS1/2.30
approaches targeting Hippo components will expand the avail- Recently, Sixian Qi et al.31 showed that this process was mediated
ability of precise therapies against cancers and other diseases. To by WWC proteins (WWC1/2/3), which act as scaffold proteins.
date, a multitude of laboratory investigations has been performed Besides, except for MST1/2, MAP4K family proteins have also been
to assess the therapeutic value of these strategies in vitro and reported to participate in the activation of LATS1/2 without the
in vivo. Furthermore, some of these strategies have already been direct involvement of SAV.32–35 Thus, the activation of MST1/2 or
evaluated in clinical trials. MAP4K proteins is an initiating signal for the Hippo pathway.

1
Breast Disease Center, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17,
South of Renmin Road, 610041 Chengdu, China; 2Department of Pediatric Nephrology Nursing, Key Laboratory of Birth Defects and Related Diseases of Women and Children,
Ministry of Education, West China Second Hospital, Sichuan University, 610041 Chengdu, China and 3Department of Pharmacology and Moores Cancer Center, University of
California, San DiegoLa Jolla, CA, USA
Correspondence: Ting Luo ([email protected]) or Min Luo ([email protected])
These authors contributed equally: Minyang Fu, Yuan Hu, Tianxia Lan.

Received: 24 June 2022 Revised: 9 September 2022 Accepted: 9 September 2022

© The Author(s) 2022

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Fig. 1 A timeline of essential discoveries and processes of the Hippo pathway. These discoveries were made initially in 1995 and then
gradually to the present. The discoveries mainly focus on two aspects, including the components and processes of Hippo pathway and the
function of Hippo pathway in physiological and pathological conditions

The combined depletion of these three types of proteins has been documented that the polarity of cells acts as a key regulator of
shown to drastically block downstream signalling.36 the Hippo pathway.29 Generally, there are two types of cell
MOB1 A/B plays dual roles in Hippo activation. First, MOB1A/B polarity: apicobasal polarity (AP) and planar cell polarity (PCP).
functions as a scaffold that contributes to the interaction between While AP divides the plasma membrane into the apical domain
MST1/2 and LATS1/2. Second, phosphorylated MOB1 A/B can and basal domain,58 PCP refers to the polarization of epithelial
directly promote the activation of LATS1/2 by inducing a cells along an axis perpendicular to the apical–basal axis (from
conformational change in LATS.37,38 LATS1 and LATS2 are serine/ proximal to distal).59
threonine kinases in the AGC kinase family. Upon activation, they Notably, a wide spectrum of proteins on apical and basal
directly interact with downstream YAP/TAZ. It was suggested that domains or within the cell junction complexes have been reported
this interaction might be mediated by WW domains on YAP/TAZ to be upstream mediators of the Hippo pathway cascade.60 For
and PxY motifs on LATS1/2.29,39,40 Compelling evidence suggests example, in Drosophila, the tumour suppressor Merlin/neurofibro-
that activated LATS1 and LATS2 phosphorylate and inactivate YAP min-2 (Mer/NF2) localizes at the apical domain and functions as a
and TAZ,41 the main downstream effectors of the Hippo pathway. linker for the actin cytoskeleton and plasma membrane.61 Mer/NF2
When the Hippo pathway is activated, the activity of YAP/TAZ is contributes to the recruitment of Hippo kinase and participates in
inhibited through LATS1/2-mediated phosphorylation. When the the activation of the Hippo pathway.62 Additionally, posttransla-
Hippo pathway is inactivated, dephosphorylated YAP/TAZ translo- tional modifications of Mer/NF2, such as NEDD4L-mediated
cates into the nucleus and binds to the transcription factors ubiquitination, have been shown to be required for the activation
TEAD1-4 to induce gene expression.42 TEAD1-4 could function as of Lats1.63 In mammals, it has been demonstrated that the cataract
transcriptional repressors by recruiting vestigial-like (VGLL) family formation phenotype in NF2-deficient mice could be suppressed by
proteins, such as VGLL343 and VGLL4.44,45 These factors competi- the depletion of the Yap gene.64 In another study, the connection
tively bind to TEAD and YAP/TAZ and cause transcriptional silencing. between NF2 and YAP was evaluated in the mouse myocardium.65
However, uncontrolled activation of YAP/TAZ and TEAD1-4 could It was shown that the expression level of YAP was upregulated in
lead to constitutive activation of this pathway, thereby leading to the cardiomyocytes of cardiomyocyte-specific NF2-knockout mice.
pathological consequences.46–48 Moreover, NF2-deficient mice were resistant to H2O2-induced
ischaemia/reperfusion (I/R) injury in the heart.65 In addition, Yap
Upstream signals of the Hippo pathway depletion could diminish the protection against I/R in
Because of the important biological roles of the Hippo pathway, cardiomyocyte-specific NF2-knockout mice, indicating that NF2
considerable efforts have been made to examine the upstream regulates the activity of YAP.65 Additionally, Scribble (Scrib) is a
signals that regulate the Hippo kinase cascade.5 To date, a large membrane protein localized on the basal domain. In Drosophila, the
number of such signals have been identified.20,49–52 In this enhancement of cell migration induced by the inhibition of Scrib
review, these signals are classified into five subgroups: cell was shown to be mediated by Yki.66 Furthermore, it was shown that
polarity, mechanical cues, cell density, soluble factors, and stress cancer-associated phenotypes may be induced by the interaction
signals53–57 (Fig. 3). between Scrib and Yap, which inhibits the activity of YAP.67
In addition, apical and basal domains are physically separated by
Cell polarity. Cell polarity refers to distinct spatial characteristics cell junction complexes. Many cell junction proteins have also been
with respect to the shape and structure of cells. It is well shown to play regulatory roles in the Hippo pathway by interacting

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Fig. 2 The core Hippo pathway in mammals. STRIPAK complex in the upstream regulates both MST1/2 and MAP4Ks. MAP4Ks or MST1/2 and
its scaffold protein SAV1 could phosphorylate LATS1/2 and its scaffold MOB1 with the help of WWC1–3. The phosphorylated MOB1 can also
directly promote the activation of LATS1/2 by inducing the conformational change of LATS1/2. The activated LATS1/2 phosphorylated and
inactivated YAP/TAZ, preventing it from translocating into the nucleus and binding to transcription factors TEAD1–4

with Hippo components.68,69. For example, the angiomotin (AMOT) Hippo pathway, cells sense and respond to mechanical cues such
family of proteins (AMOT, AMOTL1, and AMOTL2) are essential for as extracellular matrix (ECM) stiffness, cell geometry, liquid flow
tight junctions and cell polarity.70 It was reported that AMOT forces,85 tension and attachment. These mechanical cues have
proteins function as scaffolds for LATS1/2, facilitating the phos- strong effects on the proliferation, survival, and differentiation of
phorylation of LATS1/2 by MST1/2. Moreover, AMOT contributes to cells through the Hippo pathway.84
the connection between LATS1/2 and YAP, which is required for the Changes in ECM stiffness represent an important type of
activation of YAP.71 In addition, α-Catenin is an essential mechanical cue. It was reported that the Ras-related GTPase RAP2
component of the E-cadherin–catenin complex, and its function is could be activated by low ECM stiffness, which leads to the
of vital importance for the integrity of adherens junctions.72 It has activation of LATS1/2.86 Additionally, Agrin, an ECM proteoglycan
been shown that α-Catenin can inhibit the nuclear localization of that binds to lipoprotein-related receptor-4 (Lrp4) and muscle-
YAP. This inhibitory role is associated with the tumour-suppressive specific kinase (MuSK), has been reported to relay matrix rigidity
effects of α-Catenin.73 In addition, Zonula occludens (ZO) proteins signals to the Hippo pathway by interrupting the functioning of
(ZO-1, ZO-2, ZO-3) are scaffolding proteins that provide a structural Merlin and LATS1/2.87 Moreover, it was revealed that the aberrant
basis for tight junctions.74 It has been shown that ZO-2 silencing expression of tenascin C leads to the repression of ECM adhesion
leads to the activation of YAP and causes renal hypertrophy.75 forces and activation of the Hippo pathway, thereby facilitating
Finally, PCP, another type of cell polarity, also functions as an new bone formation.88
upstream signal of the Hippo pathway. It has been demonstrated Additionally, changes in cell geometry could affect the activity
that PCP is regulated by the protocadherins Fat (Ft) and Dachsous of the Hippo pathway cascade. It has been observed that YAP/TAZ
(Ds),76,77 which are involved in the regulation of the Hippo tends to localize in the nucleus in murine myoblasts with a
pathway.78,79 Through the Golgi-resident kinase four jointed (FJ), rectangular shape.89 When myoblasts are in an elongated
Ft and Ds engage with each other heterophilically between cells. In rectangular shape, the ratio of cytoplasmic to nuclear YAP/YAZ
addition, the Ft–Ds system functions as a ligand‒receptor pair for is increased.89 This finding suggests that the geometry of cells can
the Hippo pathway.5 Notably, it was shown that the regulatory affect the distribution of YAP/TAZ by regulating the activity of the
effect of the Ft–Ds system on the Hippo pathway is regulated by Hippo pathway. In addition, in NIH-3T3 mouse embryonic
the steepness of Ds–Fj gradients. While a shallow gradient activates fibroblasts, similar geometry-mediated regulation of the Hippo
the Hippo pathway, a steep gradient inhibits the activity of the pathway was identified. It was shown that YAP accumulates in the
Hippo pathway.80 Additionally, it was revealed that Dachs, an nucleus in flat spread cells, while in round compact cells, YAP
important downstream effector of Fat, plays key roles in the localizes in the cytoplasm.90
regulation of the Hippo pathway.81,82 It was reported that Dachs Liquid flow force represents another upstream mechanical cue
could influence the activity of the Hippo pathway by competing that regulates the Hippo pathway. It is noteworthy that a
with Mats for binding to Warts.83 substantial proportion of human body fluids are flowing liquids
such as blood and lymph.91 As a consequence, many cells are
Mechanical cues. Mechanical cues are important signals by which exposed to different levels of liquid shear stress. Compelling
cells sense their microenvironment. Through mechanotransduc- evidence suggests that cells respond to liquid shear forces
tion systems, cells can translate mechanical cues into biochemical through the Hippo pathway.92,93 The first study that uncovered
signals to control their behaviour. As early as 2011, Sirio Dupont the relationship between liquid shear forces and the regulation of
et al.84 revealed the essential role of YAP/TAZ in the mechan- the Hippo pathway revealed that increased fluid flow promoted
otransduction system. This finding suggests a tight connection the expression of YAP and was associated with osteogenesis and a
between the Hippo pathway and mechanical cues. Through the decrease in adipogenesis in mesenchymal stem cells (MSCs). In

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Fig. 3 Regulation of the Hippo pathway by upstream signals. a Five subgroups of upstream signals including cell polarity, mechanical cues,
cell density, soluble factors, and stress signals are responsible for the regulation of Hippo pathway. b–f The detailed upstream signals of Hippo
pathway in every subgroup

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chondrocytes, increased fluid flow leads to increased expression of that GPCR ligands such as thrombin or lysophosphatidic acid
YAP and results in dedifferentiation.94 (LPA) could activate YAP in fibroblasts and sensitize them to TGF-
Cytoskeleton tension and cell‒cell attachments, which are β1.120 Additionally, sphingosine-1-phosphate (SIP) is a ligand of
mechanical forces, are also implicated in the upstream regulation GPCR. SIP can induce the nuclear localization of YAP and promote
of the Hippo pathway. Several regulator proteins, such as Rho, jub the expression of YAP target genes in mouse embryonic cells and
and Ajuba LIMD1, take part in the transmission from tension and liver cells.119 In addition to thrombin, LPA, and S1P, a large
attachment of cells to the Hippo pathway. It was reported that number of soluble factors have been shown to regulate the Hippo
Rho participates in the regulation of cell attachment-induced YAP pathway by interacting with GPCRs, such as Oestrogen,121
dephosphorylation.95 Moreover, it was shown that the activity of Endothelin-1,122 Angiotensin II,123 and Prostaglandin E2.124
Rho plays a pivotal role in the cell attachment-dependent Additionally, an investigation by Rui Gong et al.125 showed that
regulation of the Hippo pathway.96 The protein Jub, which can protein kinase C (PKC) is one of the major effectors downstream
negatively regulate Warts within the Hippo pathway, was shown of GPCRs that modulate YAP activity.
to regulate Yki activity in response to cytoskeletal tension.97 In In addition, some soluble factors have been shown to affect the
addition, the Ajuba family protein LIMD1 and the contractile Hippo pathway independent of GPCRs. For example, it was
protein spectrin participate in cytoskeleton tension-mediated reported that IL-17A could induce the recruitment of MST1 to
Hippo pathway changes.96,98 TRAF3 interacting protein 2 (TRAF3IP2) in HaCaT and NHEK cells.
In summary, different mechanical cues are involved in the Then, the MST1–LATS1 interaction is inhibited, leading to the
upstream regulation of the Hippo pathway. Although it has been dephosphorylation of YAP. This mechanism has been shown to
found that integrin,99 peizo100 and plexin101 can act as facilitate cell proliferation in psoriasis.126 Furthermore, glucocorti-
mechanical sensor proteins that transmit signals to the Hippo coid receptor signalling has been shown to participate in the
pathway, the comprehensive molecular mechanism by which regulation of the Hippo pathway. Glucocorticoids were shown to
cells sense mechanical signals and change cellular behaviours elevate the expression of fibronectin, thus leading to cytoskeleton-
through the Hippo pathway is still unclear. The proteins in cell‒ dependent YAP activation in human breast cancer.127 Additionally,
cell contact sites and the cytoskeleton might play critical roles in transforming growth factor-beta (TGF-β) was shown upregulate
the signal transmission between mechanical cues and the Hippo TAZ levels in mesenchymal and epithelial cells. A mechanistic study
pathway cascade.102 Notably, although the mechanisms by revealed that inhibiting p38 MAPK signalling suppressed TAZ
which mechanical cues affect the Hippo pathway cascade have upregulation in response to TGF-β.128 In addition, supressing
yet to be fully understood at the molecular level, one of the core myocardin-related transcription factor (MRTF) represses TAZ
components of the Hippo pathway, YAP/TAZ, is a vital mediator upregulation induced by TGF-β. These results suggest that TGF-β
of mechanical cues.103 can regulate the Hippo pathway through p38- and MRTF-mediated
signalling.128 Other soluble factors that influence the activity of the
Cell density. It is frequently observed that the proliferation rate of Hippo pathway include bone morphogenic proteins,129 IL-6,130
cells is negatively correlated with cell density in the monolayer insulin/insulin-like growth factors,131 epidermal growth factors,132
culture. This phenomenon was shown to be associated with cell–cell and vascular endothelial growth factors.133
contact.104 It was shown that high confluence of mammalian cells
leads to the activation of LATS and the phosphorylation and Stress signals. Cellular stress, such as hypoxia, endoplasmic
inactivation of YAP. Furthermore, the overexpression of YAP could reticulum (ER) stress, energy stress, osmotic stress or heat stress,
reverse the growth inhibition induced by cell density, suggesting a can act as upstream signals of the Hippo pathway, subsequently
critical role of YAP in cell contact inhibition.105 regulating the behaviours, survival, and metabolism of cells. The
The mechanisms by which the Hippo pathway is regulated by cell mechanisms by which cells sense and transmit these signals to
density have yet to be completely elucidated. Thus far, several Hippo components have been extensively examined.134–136
complexes or proteins have been reported to function as sensors Hypoxia is a condition in which the cell has a limited oxygen
that transmit cell density signals to the Hippo pathway.5,106 It has supply. In epithelial ovarian cancer cells, it was observed that 1%
been demonstrated that cell density can be sensed by the Crumbs O2 or hypoxia mimics downregulated YAP phosphorylation (S127)
complex, which includes AMOT. The Crumbs complex interacts with but upregulated TAZ phosphorylation (S69), suggesting that
YAP/TAZ and facilitates its phosphorylation. This phosphorylation hypoxic conditions could differentially mediate the activities of
results in the suppression of the TGF-β-SMAD signalling pathway YAP and TAZ.137 Additionally, it has been reported that the
and leads to epithelial-to-mesenchymal transition.68 A recent study regulation of the Hippo pathway by hypoxia is mediated by
revealed that Kirre-like Nephrin Family Adhesion Molecule 1 Zyxin,138 SIAH2 ubiquitin E3 ligase,139 and hypoxia-inducible
(KIRREL1), a cell adhesion molecule, acts as a feedback regulator factor 1 subunit alpha (HIF-1α).140 ER stress is induced by the
of the Hippo pathway in mammalian cells. It was shown that accumulation of misfolded proteins in the ER when cells are
KIRREL1 could sense cell‒cell interactions and mediate the exposed to an unstable or adverse environment.141 In human
recruitment of SAV1 to cell‒cell contact sites. KIRREL1 knockout hepatocellular carcinoma cells, ER stress has been shown to inhibit
led to the activation of YAP.107,108 Recently, integrated screens the activity of YAP and enhance apoptosis by promoting the
revealed KIRREL as a cell surface tumour suppressor involved in the assembly of the GADD34/PP1 complex.142 Energy stress is
Hippo pathway that could bind directly to SAV1 to activate this characterized as a disruption of the homoeostasis of cellular
pathway.109 In addition, it was shown that the palmitoylation of energy. AMP-activated protein kinase (AMPK) functions as a sensor
TEAD was also regulated by cell density.110 Reportedly, other cell of energy stress. It has been demonstrated that energy stress
density transmitters for the Hippo pathway include E-cadherin,111 could induce AMPK-dependent Lats activation and lead to the
annexin A2,112 and the polarity-regulating kinase PAR1b.113 phosphorylation of YAP.143,144 This finding has been used to
explain the observation that metformin, an antidiabetic drug that
Soluble factors. Soluble factors regulate the majority of biologi- interacts with AMPK, exerts anticancer effects.134 Additionally,
cal and physiological processes. To date, numerous soluble osmotic stress caused by sorbitol treatment can induce a dynamic
factors have been shown to influence the activity of the Hippo balance between YAP activation and inhibition. In 2017, Hong
pathway.4,114 Notably, G protein-coupled receptors (GPCRs) make et al.145 discovered that osmotic stress induced the phosphoryla-
up the largest family of membrane receptors for soluble factors in tion of YAP at Ser128 by Nemo-like kinase (NLK), which then
mammals.115 The Hippo pathway has been shown to be interfered with its binding with 14-3-3, resulting in YAP nuclear
regulated by GPCR signalling.116–119 For example, it was shown accumulation and activation. Moreover, osmotic stress inhibits

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Fig. 4 The essential physiological function of Hippo pathway. The Hippo pathway effectors YAP/TAZ can take part in the modulation of
multiple cell events, including proliferation, apoptosis, differentiation and growth, thereby participating in the physiological processes of
embryogenesis and development, as well as tissue/organ regeneration and wound healing

YAP through phosphorylation at Ser127, and the underlying specific cell differentiation in a variety of tissues and organs,
molecular mechanism was further investigated by the same team including the pancreas, lung, muscle and mammary glands. For
in 2020.146 The researchers found that osmotic stress could example, pancreatic-specific Mst1/2-knockout mice were shown to
change the cell membrane distribution of phosphatidylinositol- exhibit acinar cell dedifferentiation to ductal cells, which was
4,5-bisphosphate [PI(4,5)P2], leading to the plasma membrane mediated by the hyperactivation of YAP.163 In the developing
recruitment of neurofibromin 2 (NF2), also known as merlin, to human lung, Mst1/2 deletion and YAP activation were first shown
induce downstream Hippo pathway activation.146 Moreover, heat to affect epithelial progenitor cell differentiation.164,165 In addition
stress is an important upstream signal of the Hippo pathway. Min to airway epithelial progenitors, YAP is also required for the
Luo et al.147 revealed that heat stress inhibited LATS kinase by differentiation of proximal airway166 or airway basal stem cells167 in
interacting with HSP90 and PPP5, thereby activating YAP/TAZ to adult lungs. The role of YAP-LATS in the differentiation of type I168
induce the heat shock transcriptome. or type II169 alveolar epithelial cells was further confirmed in
bronchopulmonary development. However, YAP overexpression
Critical physiological functions of the Hippo pathway promotes myoblast differentiation170 and conversely represses the
While the Hippo pathway first drew attention for its critical role in differentiation of satellite cells of skeletal muscle.171 Further studies
the control of organ size in Drosophila, over a decade of intense indicated that the absence of YAP/TAZ causes the loss of the
research has confirmed its widespread physiological roles in human differentiated contractile phenotype in vascular smooth muscle
health, ranging from decisions regarding cell fate determination cells (VSMCs) and osteogenic differentiation.172 Chen Q et al.173
during embryonic development to tissue/organ regeneration and identified that Sav1 deletion or Yap overexpression could prevent
wound healing (Fig. 4). the differentiation of mammary cells. In contrast, McNeill et al.174
discovered that YAP/TAZ activation by Lats1/2 deletion could
Cell growth, proliferation and differentiation. YAP/TAZ are key promote the differentiation of nephron progenitor cells into
downstream effectors of the Hippo pathway that can translocate interstitial myofibroblastic cells in the kidney. In addition to the
to the nucleus to induce the TEAD-mediated expression of genes aforementioned cells, the Hippo pathway has also been reported to
related to cell growth and proliferation.21,148 regulate specific cell differentiation in other tissues or organs, such
The Hippo pathway has been shown to restrict the proliferation as skin keratinocytes,154 intestinal epithelial cells,175 hepatocytes
of cardiomyocytes,10,149 the molecular mechanism in which and biliary cells.176,177
involves the Wnt150 or Pi3kcb-mediated PI3K-AKT151 signalling Overall, these findings suggest that Hippo pathway components,
pathways. The dystrophin–glycoprotein complex (DGC) was further especially YAP/TAZ, are involved in cell growth/proliferation and
shown to inhibit cardiomyocyte proliferation by directly binding differentiation in different tissues or organs under diverse contexts.
with Yap.152 Marta Diez et al.153 showed that 96 screened miRNAs
could stimulate human iPSC-derived cardiomyocyte replication by Embryogenesis and development. Embryogenesis in mammals
inhibiting the Hippo pathway. In addition, in human and mouse involves several essential stages, including preimplantation,
skin, YAP-TEAD activation promotes the proliferation of keratino- gastrulation, neurulation and organogenesis. The formation of
cytes to maintain skin homoeostasis154,155 or mediate IL-17A-driven the blastocyst is one of the important events in the preimplanta-
psoriasis.126 Moreover, the Hippo pathway regulates contact- tion stage, which consists of the outer epithelial trophectoderm
dependent cell growth and proliferation in cancer cells,156,157 (TE) and the inner cell mass (ICM). The specification of TE and ICM
nervous Schwann cells,158 epidermal stem cells159 and hepatic160 is a key event in early embryogenesis,178 and many studies have
or lung epithelial cells.161,162 revealed the contribution of Hippo components to this process.
In addition to the role of the Hippo pathway in cell growth/ For example, nuclear YAP was shown to be restricted in outside
proliferation control, this pathway has also been shown to affect cells and drives TEAD4-mediated cdx2 expression to take part in TE

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specification.179 Similarly, GATA binding protein 3 (GATA3) was In the liver, Yap1 activation in hepatocytes contributes to
shown to be regulated by TEAD4 to promote the differentiation liver regeneration.199 Additionally, the nuclear accumulation of
into TE.180 Unlike the outside cells of the morula, WWTR1/YAP1 Yap1 was increased in proliferating hepatocytes after partial
was repressed by LATS1/2 to permit the expression of SOX2 in the hepatectomy, which facilitated the epithelial–mesenchymal
inside cells. The deletion of LATS1/2 leads to the accumulation of transition (EMT) for liver regeneration.200 Additionally, blocking
nuclear YAP in inner cells and causes abnormalities in the ICM and MST1/2 effectively enhanced liver repair and regeneration. 201 It
changes the cell fate towards TE-like.181,182 Similarly, inhibiting the is commonly believed that the regenerative capacity of
upstream actor NF2 causes the mislocalization of YAP and alters mammalian hearts is lost after the neonatal stage.202 However,
the production of CDX2 inside cells.183 In summary, in morula, the recent evidence suggests that YAP activation can induce
Hippo pathway is highly activated in inside cells, whereas Hippo is cardiac regeneration in adult mice.10,190,203,204 Several investi-
in a low activation state in outside cells to maintain the normal gations have been conducted to examine the mechanisms by
specification of TE and ICM in the preimplantation stage. which YAP/TAZ mediate cardiac regeneration. For example,
Following the preimplantation stage, embryo development Yap activates the insulin-like growth factor (IGF) signalling
enters the gastrulation and neurulation stage on Day 26 in pathway to augment the proliferation of cardiomyocytes.205 In
humans and embryonic Days 6 (E6) to 9 (E9) in mice.178 YAP−/− addition, Yap activation was shown to be associated with EMT
embryos showed defects in the yolk sac vasculature on E8.5, which during cardiac regeneration.206 In the context of lung
indicates that the Hippo pathway may contribute to angiogenesis regeneration, it was reported that in alveolar stem cells, Yap
in the gastrulation and neurulation stages.184 The relationship is activated after pneumonectomy, which plays a critical role in
between angiogenesis and the Hippo pathway has already been alveolar regeneration.207 Moreover, it was observed that lung
widely discussed.133,185 However, the detailed underlying mechan- regeneration is substantially delayed in mice that lack Yap/Taz
ism by which Hippo contributes to angiogenesis in this stage is in alveolar epithelial type II cells.208 In addition to these organs,
unclear and should be further studied. activation of YAP/TAZ has been shown to contribute to
After the gastrulation and neurulation stages, at approximately regeneration in many other tissues, such as the nervous
3–8 weeks in humans, organogenesis occurs.178 It has already been system209–211 and bone. 212
shown that the development of organs such as the heart, lung, and The roles of the Hippo pathway in wound healing have been
kidney is related to the Hippo pathway. In terms of cardiac extensively examined.213–215 Notably, the Hippo pathway affects
development, von Gise et al.186 reported that YAP could contribute wound healing through various mechanisms. For example, the
to cardiac development by inducing cardiomyocyte proliferation. activation and nuclear localization of YAP/TAZ promote prolifera-
Deletion of Yap1 in foetal cardiomyocytes leads to lethal cardiac tion in epithelial cells during wound healing.213,216 Additionally,
hypoplasia. Conversely, inactivation of the Hippo pathway, such as TEAD inhibition increases Kruppel-like factor 4 (KLF4) levels and
through Yap1 activation or Salv, Lats2 and Mst1/2 knockout, causes disrupts skin homoeostasis, thus impairing wound healing.154 In
cardiomegaly.150,186 For lung development, YAP is essential for the addition, wound-healing-related epithelial–mesenchymal transi-
proper morphogenesis of the airway. Severe branching morpho- tion (EMT) was shown to be regulated by YAP/TAZ in mice.217
genesis disruptions occur when the expression of YAP is Furthermore, the inhibition of YAP was shown to promote the
blocked.187 Moreover, the deletion of both Mst1 and Mst2 causes expression of IL-33 and then lead to autophagy inhibition, which
severe lung abnormalities, resulting in death at birth.164 Further- contributes to wound healing.218
more, the Hippo pathway plays an important role in kidney Collectively, embryonic development and adequate and
development. It has already been reported that YAP is essential for efficient tissue regeneration require highly controlled and
nephrogenesis, while NF2 and LATS are needed for the harmonious cell proliferation, as well as cell differentiation.
morphogenesis of ureter branching.188,189 Considerable efforts should be devoted to understanding the
complex molecular mechanisms by which YAP/TAZ mediate these
Tissue/organ regeneration and wound healing. The Hippo path- critical physiological functions.
way plays pivotal roles in tissue/organ regeneration and wound
healing.190 While tissue/organ regeneration is an important Dysregulation of the Hippo pathway and human diseases
biological process that makes tissues/organs resilient to damage As a signalling pathway that governs the proliferation, differentia-
and disturbances, wound healing refers to the process by which tion, and survival of cells, the Hippo pathway plays a vital role in the
the skin repairs itself after injury.191 Recent evidence suggests that development and homoeostasis of organs. Therefore, dysregulation
YAP/TAZ, the key component of the Hippo pathway, is activated of the Hippo pathway causes a variety of diseases, including cancer,
after damage to the skin or a variety of organs, such as the eye diseases, cardiac diseases, pulmonary diseases, renal diseases,
intestine, liver, heart, and lung.192 hepatic diseases, and immune dysfunction (Fig. 5). In this section,
The role of the Hippo pathway in intestinal homoeostasis and the consequences of aberrant Hippo pathway function in human
regeneration is controversial and multifaceted.192 Generally, YAP/ diseases will be discussed.
TAZ is crucial and indispensable for intestinal tissue regeneration
after injury in both Drosophila and mice.193 Many studies have The Hippo pathway in cancer. The hypothesis that the Hippo
reported that the level of YAP protein in the intestinal epithelium pathway has a close connection with cancer was initiated by the
is highly increased during intestinal regeneration and that its discovery that the egregious overgrowth of Drosophila melano-
inactivation severely compromises this regenerative pro- gaster tissues could be caused by Hippo gene mutations.219–221
gramme.194,195 In addition, the self-renewal and regeneration of Overwhelming evidence suggested that the Hippo pathway was
the intestine are dependent on intestinal stem cells (ISCs), which one of the most frequently dysregulated pathways in human
are positive for leucine-rich repeat-containing GPCR5 (Lgr5)196 and cancer; YAP/TAZ were commonly identified as oncoproteins,
mainly express YAP.194 YAP promotes intestinal regeneration by while MST1/2 and LATS1/2 were identified as tumour suppres-
suppressing Wnt signalling in Lgr5+ ISCs.197 Conversely, an sors.222–225 Cancers such as uveal melanoma,226 mesothe-
inhibitory effect of YAP on intestinal regeneration was discovered lioma,227 ependymoma,228 and NF2-related schwannomas229
by Barry et al.194. The discrepancy in Wnt inhibition by YAP/TAZ have all been shown to be related to Hippo pathway dysregula-
may contribute to the inconsistent results. Furthermore, the tion. Generally, the Hippo pathway can affect human cancer in
inactivation of YAP/TAZ in mouse intestines resulted in no visible three ways: tumour initiation and progression, tumour metastasis,
abnormalities, suggesting that YAP is not indispensable for normal and tumour drug resistance. The detailed underlying mechan-
intestinal development and homoeostasis.195,198 isms will be discussed below.

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Fig. 5 The summary of diseases caused by the dysregulation of the Hippo pathway. Hippo pathway dysregulation has been found to be
present in a variety of organs or systems diseases and involved in the regulation of occurrence or progression of these diseases. The specific
diseases are shown in boxes

The Hippo pathway in tumour initiation and progression: role in tumorigenesis. Further evaluation of this relationship in the
Tumour initiation and progression is a multistep process that occurrence and development of different types of tumours is
is characterized by the transformation of normal cells to essential for the development of precise Hippo-related treatments.
malignant tumour cells and is triggered by multiple factors.
One of these factors is the dysregulation of signalling pathways The Hippo pathway in tumour metastasis: Tumour metastasis
related to cellular survival.230 Because the Hippo pathway is an is known as a multistep process that is associated with a higher
essential survival-associated signalling pathway, inactivation of level of malignancy. Accumulating evidence suggests that Hippo
this pathway could increase cell proliferation and decrease pathway components, including LAT1/2, MST1/2, YAP and TAZ,
apoptosis, contributing to tumour initiation and progres- may play important roles in influencing tumour metasta-
sion.3,219 Tumour initiation and progression require metabolic sis.235,239–244 Furthermore, the Hippo pathway was shown to
reprogramming.231 Some researchers have reported that the influence various types of metastases. Lung and lymph nodes
Hippo pathway participates in cancer-related metabolic repro- are two common sites of breast cancer metastasis, while the
gramming, such as glycolysis, which requires tumour cells to brain is a common site of lung cancer metastasis.245,246 in YAP-
obtain the necessary energy and building blocks and can be deficient PyMT mice, which is a breast cancer model, the
promoted by active YAP.144,232 incidence of lung metastasis was reduced.173 In a breast tumour
Cancer stem cells (CSCs), which are a subpopulation of cancer with high lymph node metastasis, the expression of LATS1/2
cells, play an important role in tumour initiation and progres- decreased cancer metastasis.241 In addition, YAP inhibition could
sion.233 In a recent study, the Hippo pathway component TAZ markedly decrease H2030-BrM3 cell brain metastasis in vivo.247
potentiated CSCs. Depletion of TAZ significantly decreased the In most cases, the Hippo pathway may act as an inhibitor of
tumour-seeding ability.234 Thus, the Hippo pathway contributes to tumour metastasis; thus, it represents a potential target for
tumour initiation and progression by regulating CSCs. antitumor metastasis therapies.
However, a few recent studies have presented some opposing The underlying mechanism by which the Hippo pathway affects
ideas. In certain types of tumours, the Hippo pathway may change tumour metastasis can mainly be divided into two parts. First, the
from a tumour suppressor to a tumour promoter. Cheung et al.235 Hippo pathway can regulate the migration and invasion of cells.
found that YAP plays a suppressive role in colorectal tumour Epithelial-to-mesenchymal transition (EMT) is a significant char-
growth. YAP overexpression hindered both primary and meta- acteristic of cancer cells with enhanced migration.248 Activated
static colorectal cancer. Similar tumour suppressive activity of YAP/TAZ can increase the expression of EMT-related transcription
YAP/TAZ was observed in ER+ breast cancer,236 haematological regulators.20,249 In contrast, Hippo pathway inactivation can play
cancers237 and several solid cancers of neural/neuroendocrine suppressive roles against the migration and invasion of cells. For
origin.238 In addition, deletion of the tumour suppressor’ LATS1/2 example, YAP knockout promotes breast cancer lung metasta-
in cancer cells inhibits tumour growth in B16, SCC7 and 4T1 sis.194,250,251 Second, the Hippo pathway could contribute to
immunocompetent syngeneic mouse models in vivo due to tumour metastasis by suppressing anoikis, a form of apoptosis
enhanced immunogenicity of the cancer cells.41 These findings induced by the loss of attachment between cells and the ECM. It
suggest that the Hippo pathway may play a tissue type-specific was revealed that LIM domain only 3 (LMO3) could inhibit anoikis

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to promote hepatocellular carcinoma metastasis by suppressing V600E, while the MEK inhibitor alone can not induce this effect.282
the Hippo pathway.252 Clinically, the increased YAP levels may decrease the efficacy of
MEK inhibitors.282 Ultimately, in terms of EGFR tyrosine kinase
The Hippo pathway in the development of tumour drug inhibitor resistance, TAZ expression is one of the intrinsic
resistance: Multiple therapies have been developed to treat mechanisms. The overexpression of TAZ in PC9 cells reduced
cancers. In particular, chemotherapy, immunotherapy, and their sensitivity to gefitinib. TAZ knockdown sensitized gefitinib-
targeted therapy are the three main anticancer therapies. resistant PC9/GR cells to gefitinib.283 Moreover, other targeted
However, the efficacy of these treatments is severely impaired therapies, such as mTOR and CDK4/6 inhibition therapy, were
due to tumour drug resistance.253–255 Compelling evidence has shown to be related to the Hippo pathway.284,285
shown that the Hippo pathway contributes to the development
of chemotherapy resistance. The main four Hippo components, The Hippo pathway in eye diseases. The connection between the
YAP, TAZ, MST1 and LATS1/2, were all shown to take part in the Hippo pathway and the development of the eye has been studied
development of chemoresistance.256 For example, YAP and TAZ for many years. In many ocular tissues such as the cornea, lens and
overexpression or YAP nuclear translocation could decrease the retina, YAP was shown to be ubiquitously distributed.286
efficacy of cisplatin,257, doxorubicin,258 5-fluoracil259,260 and Additionally, it was reported that the Hippo pathway may play
Taxol,261 while MST1 and LATS1/2 downregulation resulted in an indispensable role in regulating retinogenesis, retinal neuro-
resistance to cisplatin262 and 5-fluoracil.263 genesis, retinal angiogenesis, and corneal wound healing,
The underlying mechanism of chemotherapy resistance may suggesting that the Hippo pathway is involved in the regulation
be connected to the stemness of cancer cells or drug metabolism of ocular development.287–290 Therefore, dysregulation of the
and efflux. First, the Hippo pathway could affect chemotherapy Hippo pathway substantially disrupts eye homoeostasis and
resistance by regulating CSCs. CSCs, which are tumour-initiating results in different types of eye diseases.
cells, are a subgroup of cancer cells that could contribute to In general, changes in the Hippo pathway in eye diseases are
chemoresistance. The Hippo pathway is an important pathway relatively complex. Hippo pathway dysregulation seems to be
that regulates CSCs234,264–266. In ovarian cancer, the overexpres- common in retinal-related diseases. In the retinas of mice with
sion of miR-30b and the downregulation of MYPT1 were shown to diabetic retinopathy, LATS and TAZ were increased, and p-MST
cause the expansion of CSCs by inactivating the Hippo pathway, and p-YAP were significantly decreased.291 In addition, in patients
ultimately resulting in platinum resistance264. In addition, the with Sveinsson’s chorioretinal atrophy, the Tyr421His mutation in
Hippo pathway was shown to be related to drug metabolism and TEAD1 has been found, and this mutant Tyr421His TEAD1 has a
efflux, which is an important factor in determining the efficacy of compromised interaction with YAP.148,292 Moreover, MST2 but not
chemotherapy drugs. The increased efflux and metabolic MST1 was identified as a factor that causes retinal detachment-
conversion of a drug will decrease its efficacy considerably by induced photoreceptor cell death. MST2 deficiency could prevent
reducing intracellular drug concentrations267. It was reported that photoceptor cells from death after retinal detachment.293
YAP activation could sensitize pancreatic cancer cells to In addition to retinal-related diseases, the heterozygous
gemcitabine by downregulating drug efflux transporters and inactivation of YAP1, which decreases the expression of YAP1
decreasing the conversion of gemcitabine from a less active form protein in lens epithelia, results in cataracts with lens epithelial cell
to an active form, resulting in increased concentrations of defects.294 Moreover, NF2 deficiency in the lens epithelium in
gemcitabine in tumour cells268. mice could lead to a cataract phenotype.64
In addition to chemotherapy, immunotherapy can be affected
by the Hippo pathway. Over the last decade, immunotherapy The Hippo pathway in cardiac diseases. As early as 2011, a series
has been widely examined. Immune checkpoint inhibitor of studies uncovered the role of the Hippo pathway in regulating
therapy and chimeric antigen receptor (CAR) T-cell immunother- heart size.150,205 Moreover, Wei Yu et al. identified the vital role of
apy are the most striking examples269–271. However, the efficacy VGLL4 in heart valve development. The deletion of VGLL4 in mice
of these therapies still faces challenges associated with could lead to serious valve malformation.295 These studies
resistance. Myeloid-derived suppressor cells and tumour- resulted in further studies on the connection between cardiac
associated macrophages are immunosuppressive cells in the regulation and the Hippo pathway. Among them, the effect of the
tumour microenvironment that can contribute to immunother- Hippo pathway on cardiac diseases is a hot topic. Cardiac diseases
apy resistance272–274. It was reported that the Hippo pathway that are associated with a dysregulated Hippo pathway could be
could influence these two cell types to reduce the efficacy of divided into at least four types: cardiomyopathy; heart failure;
immune therapy. YAP can directly induce cytokines such as coronary heart diseases; and myocardial infarction.296
CXCL5 and CCL2, which attract myeloid-derived suppressor cells Cardiomyopathy is a group of cardiac diseases that are
and tumour-associated M2 macrophages, respectively, to confer characterized by myocardial dysfunction. Hypertrophic cardio-
resistance to immunotherapy275,276. pathy (HCM), arrhythmogenic cardiomyopathy (ARCV) and dilated
Finally, the most important clinical implication is the involve- cardiomyopathy (DCM) are three common cardiomyopathies.297
ment of the Hippo pathway in targeted therapy resistance. There All are associated with Hippo pathway dysregulation. Samples
are currently several targeted cancer therapies, such as BRAF from patients with HCM were investigated, and YAP was shown to
inhibitors, MEK inhibitors and epidermal growth factor receptor be increased at both the protein and mRNA levels. Moreover, the
(EGFR) tyrosine kinase inhibitors. BRAF inhibitors can be used to inhibitory phosphorylation at Ser127 of YAP was decreased,
treat BRAF-mutant melanoma. However, efficacy could be limited indicating the activation of YAP.298 However, the condition seems
because of drug resistance.277,278 While exploring the mechanism to be different in ARCV299 and DCM,300 in which the Hippo
of BRAF inhibitor resistance in melanoma, researchers found that pathway was activated, leading to YAP inactivation.
the upregulation of MOB3B and activation of the Hippo pathway Heart failure is a functional and structural heart disorder with
contribute to vemurafenib resistance.279 In addition, NF2 is complex clinical syndromes that can be affected by the Hippo
involved in vemurafenib resistance.280 Regarding MEK inhibitor pathway. p-YAP and p-LATS were increased in ischaemic or
resistance, the Hippo pathway may play an essential role. In vitro, nonischaemic heart failure samples.301 In addition, TEAD1 was
the A549 and HCC44 cells that express YAP1 5SA were shown to reported to take part in the dedifferentiation of cardiomyocytes to
have selumetinib resistance.281 The combination of YAP suppres- exacerbate heart failure during pressure overload.302 The above
sion and MEK inhibition can induce apoptosis in NSCLC, studies suggest that heart failure is often accompanied by
melanoma, colon cancer and thyroid cancer harbouring BRAF abnormal Hippo pathway activation.

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In addition, the progression of coronary heart diseases and Furthermore, the Hippo pathway could take part in the
myocardial infarction may be related to changes in the Hippo formation of a fibrotic environment in the kidney. Renal fibrosis
pathway.296 YAP/TAZ activity is involved in atherogenesis, which is a is a pathophysiological hallmark of patients with chronic kidney
characteristic of coronary heart disease.303 Interestingly, specific diseases. Ischaemia‒reperfusion (IR) injury is a common model
deletion of YAP in fibroblasts can effectively reduce the fibrotic used to study the acute renal injury-chronic kidney disease
response and improve cardiac function after myocardial infarction.304 transition. In the IR injury model, YAP levels were increased
along with the progression of renal fibrosis.319 In other renal
The Hippo pathway in pulmonary diseases. The COVID-19 out- injury models with renal fibrosis, such as the obstructive,
break has resulted in a substantial focus on the relevant aristolochic acid and diabetic nephropathy models, the expres-
mechanisms of the development of lung diseases. As a signalling sion of TAZ in the tubulointerstitium was elevated.320 In
pathway that could take part in pulmonary development, the addition, MST1/2 deletion in renal tubule cells caused progres-
Hippo pathway may contribute to pulmonary diseases when it is sive renal interstitial fibrosis.319–321
dysregulated.162,305 Generally, dysregulation of the Hippo pathway
frequently occurs in the progression of three pulmonary diseases: The Hippo pathway in central nervous system disorders. Central
pulmonary arterial hypertension, inflammatory pulmonary dis- nervous system disorders are traditionally classified as early-onset
eases, and pulmonary fibrosis. neurodevelopmental and late-onset neurodegenerative dis-
First, Hippo components such as YAP and LATS1 are dysregulated eases.322 Hippo pathway dysregulation is closely associated with
in pulmonary arterial hypertension. The inactivation of Hippo could neurodegenerative diseases.323
induce proliferation and suppress apoptosis in pulmonary arterial In neurodegenerative diseases such as Alzheimer’s disease
smooth muscle cells (PASMCs), which is one of the most important (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease
factors in vasculature remodelling in pulmonary arterial hyperten- (HD), the main characteristic is the abnormal death of functional
sion.306,307 Interestingly, recent research revealed that MST1/2, a neural cells, which could be mediated by the Hippo pathway.324
Hippo component that usually plays an antiproliferative role, In AD, the Hippo pathway seems to be activated. One of the
supports the abnormal proliferation of PASMCs in pulmonary causes of AD is the accumulation of amyloid-beta 42 peptides
arterial hypertension via forehead homeobox type O and BUB3.308 (Aβ42). The activated Hippo pathway could contribute to Aβ42-
Second, the Hippo pathway could regulate the inflammatory induced neural cell death.325 Additionally, in Fused in Sarcoma
response in the lung. In a bacterial pneumonia model, the relative (FUS)-mediated ALS, activated Hippo participated in neuronal cell
levels of p-YAP and p-TAZ were decreased in alveolar epithelial death by further activating c-JUN amino-terminal kinase (JNK).
type II cells (AECIIs). YAP/TAZ activation seemed to be a protective Cell death could be rescued by downregulating the Hippo
reaction. When YAP/TAZ was deleted in AECIIs, inflammation in pathway.326 In SOD1(G93A) mice, which are a commonly used
the lung became more severe.208 Similarly, the deletion of YAP in mouse ALS model, genetic deletion of MST1 could improve spinal
lung endothelial cells could lead to inflammation in the lung.309 cord motor neuron viability and decrease mortality.327 Finally, in
In summary, activation of the Hippo pathway may contribute to HD mice, deficiency in TEAD/YAP-dependent transcription could
pulmonary inflammation. However, the connection between lead to necrotic cell death.328 In addition, LATS was activated in
other Hippo components and pulmonary inflammation needs the brains of patients with HD.329
to be further studied.
Third, Hippo can contribute to the progression of fibrotic The Hippo pathway in hepatic diseases. The Hippo pathway not
diseases in the lung. Pulmonary fibrosis is the result of many only affects the physiological regeneration of the liver but also
interstitial pulmonary diseases and is associated with activated impacts the progression of liver disease. Among the liver diseases
fibroblasts and exuberant extracellular matrix deposition. YAP that the Hippo pathway can influence, hepatitis and liver fibrosis
promotes the proliferation and migration of fibroblasts, inducing are two of the most well-documented examples.17,200,330
the production of collagen and inhibiting epithelial cell Alcoholic hepatitis (AH) and nonalcoholic steatohepatitis
differentiation, thus contributing to the progression of idiopathic (NASH) are two kinds of hepatitis that can be regulated by the
pulmonary fibrosis.310,311 Hippo pathway. In a mouse model of AH,331 YAP levels were
elevated in hepatocytes, while in liver samples from human
The Hippo pathway in renal diseases. Renal diseases have been patients with AH,332 YAP1 mRNA was increased, and the active
recognized as a serious public health burden in the past form of MST1 was decreased, indicating low Hippo pathway
decade.312 Chronic kidney diseases have a widespread impact activity in AH livers. Similarly, the levels of TAZ and YAP were
and have received much attention. Diabetic and polycystic kidney elevated in mice and human patients with NASH.333 One of the
diseases are two types of chronic kidney diseases.15,313 They are all underlying mechanisms by which YAP/TAZ is increased in NASH
related to dysregulation of the Hippo pathway. may be related to the suppression of TAZ degradation mediated
In diabetic nephropathy, the abnormal proliferation of glo- by β-TrCP-mediated ubiquitination and degradation.334
merular mesangial cells is one of the pathological characteristics. Hepatic fibrosis results from chronic liver damage, which can be
The Hippo pathway is inactivated and contributes to abnormal caused by NASH, alcohol abuse or hepatitis virus infection.335
proliferation.314 In addition, in renal enlargement, which is one of Carbon tetrachloride (CCl4) is a hepatotoxin that is widely used to
the early structural changes in diabetic nephropathy, the Hippo establish hepatic fibrosis animal models.336 In hepatic fibrosis
pathway takes part in regulating the proliferation of tubular caused by CCl4 injection, YAP was increased in the nucleus and
epithelial cells.315 cytoplasm in hepatocytes and biliary cells from fibrotic livers. After
Except for diabetes, many recent studies have highlighted YAP deletion, the expression of Col1a1 was reduced, suggesting
Hippo-YAP signalling in renal cyst formation to explain the the suppression of fibrogenesis.337 Similarly, Jie et al.338 found that
contribution of the Hippo pathway to polycystic kidney diseases, a dopamine receptor D2 antagonist, which could block YAP in
which are inherited disorders mainly caused by PKD1 or PKD2 macrophages, had the potential to attenuate CCl4-induced liver
mutations. It was reported that PKD1 deficiency in mice resulted fibrosis. However, in the IR injury model, YAP plays a protective
in YAP and TAZ activation in cystic tubular epithelia. Knockout of role against IR stress and decreases IR-induced liver fibrosis.339
YAP and TAZ in the autosomal dominant polycystic kidney Therefore, YAP has a complex role in liver fibrosis that depends on
disease model significantly suppressed cystogenesis.316,317 In the cell type and context.
pkd2 morphants, the Hippo pathway was inactivated as well, In terms of the underlying mechanism, the Hippo pathway
resulting in YAP dephosphorylation and nuclear translocation.318 could contribute to hepatitis and hepatic fibrosis by regulating the

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Table 1. The potential drugs targeting Hippo pathway in preclinical trials

Mechanism Drugs Structure/sequence Indications

YAP/TAZ nucleus/ MSTs kinase XMU-MP-1 Chronic and acute

cytoplasm location activity inhibition liver injury
Protest cancer
Breast cancer
Autoimmune
encephalomyelitis Cardiac
hypertrophy

SBP-3264 Acute myeloid leukaemia

MSTs kinase MST1/2-siRNA MST1 (5’–3’ sense GAGUGUCAAUAUUGCGAGAtt) Deficiency of liver

expression MST2 (5’–3’ sense CAAGAGUCAUGAAAAUUGUtt) regeneration
inhibition
LATs kinase TRULI No certain indication so far
activity inhibition

Sav kinase Sav-shRNA Not post Myocardial infarction

expression Ischaemic heart failure
inhibition
YAP-TEAD YAP/TAZ CA3 Oesophageal
transcriptional expression adenocarcinoma
activity regulation inhibition Osteosarcoma tumour

YAP-siRNA Not post Glioblastoma

Hepatocellular carcinoma
Posterior segment
neovascularization-related
ocular diseases
YAP-shRNA Not post Lung fibrosis

activation of hepatic stellate cells. Hepatic stellate cells are Hippo pathway in the progression of hepatic inflammation and
important hepatic cells that can secrete various inflammatory hepatic fibrosis.333,337,342
molecules and extracellular matrix components to aid the
progression of hepatic inflammation and fibrosis.340,341 The effect The Hippo pathway in immune dysfunction. The immune system
of YAP/TAZ on the activation of hepatic stellate cells has been consists of two parts: the innate immune system and the adaptive
verified in multiple studies, supporting the importance of the immune system. In the past few years, it was observed that

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Table 1. continued
Mechanism Drugs Structure/sequence Indications

YAP-TEAD verteporfin Glioblastoma

interaction Breast cancer
inhibition Hepatocellular carcinoma
Renal interstitial
fibrogenesis
Glaucoma

VGLL4- SVDDHFAKSLGDTWLQIGGSGNPK- Gastric cancer

mimiking TANVPQTVPMRLRKLPDSFFKPPE Colorectal cancer
peptide
TEAD Flufenamic Glioblastoma (in vitro)
palmitoylation acid
inhibition derivative

dysregulation of the Hippo pathway can influence both innate In the clinic, autoimmune manifestations were found in Mst1-
and adaptive immunity.18 deficient patients as well.356
Innate immunity is the first line of defence that protects the
body from infection in a nonspecific way, and the Type I interferon Therapeutic targeting of the Hippo pathway
(IFN) response, which is known as IFNα and IFNβ, is an essential The close connection between the Hippo pathway and various
defence.343,344 YAP negatively regulates IFN-β signalling. Mice diseases indicates that the Hippo pathway is an appealing
with YAP deficiency showed increased IFN-β levels compared to therapeutic target. Until now, no drug specifically targeting the
control mice after being infected with vesicular stomatitis virus Hippo pathway has been developed for clinical use, likely due to
and herpes simplex virus type 1 (HSV-1), suggesting enhanced the relatively short history of this pathway. However, potential
innate immunity. Importantly, YAP deficiency reduced the Hippo-targeted drugs have been widely investigated in both
mortality of mice after HSV-1 challenge.345 In contrast, LATS2 preclinical (Table 1) and clinical trials (Table 2).357,358 At present,
could support innate immunity by increasing INF-β expression the development of potential drugs mainly focuses on three
after human immunodeficiency virus-1 infection in vitro, and the aspects of the Hippo pathway, including Hippo core kinase
loss of LATS2 impaired the innate immune response.346 Recently, activity/expression, downstream YAP/TAZ expression levels and
LATS1 was shown to be essential in regulating the activity of type I YAP/TAZ-TEAD interactions.7 The Hippo core kinases inhibit YAP/
IFN signalling.347 TAZ to control its location and subsequently influence the
Furthermore, the Hippo pathway is important for the function expression of Hippo target genes.114 Thus, inhibitors of Hippo
of immune cells that take part in adaptive immunity. First, the core kinases can be readily developed. However, inhibiting Hippo
Hippo component Mst1/2 could affect the proliferation of naïve core kinases can result in YAP/TAZ activity, which is often
T cells and the number of peripheral T cells. Although Mst1 associated with pathogenesis, particularly cancer. This could be
deficiency did not change the process of T-cell development, it a concern, although Hippo core kinase inhibitors may promote
could decrease the thymic egress of T cells and increase the regeneration and wound healing. Furthermore, when YAP/TAZ
proliferation of naïve T cells. Double knockout of Mst1 and Mst2 translocates into the nucleus, the transcription and expression of
reduced peripheral T cells, while the deletion of Mst2 alone did Hippo-related genes depend on the interaction between YAP/TAZ
not significantly change peripheral T cell numbers.348,349 Besides, and TEAD1-4.148 YAP-TEAD transcriptional activity can be sup-
the Mst1 deficiency was shown to decrease the numbers of pressed by reducing the expression of YAP/TAZ, disrupting the
marginal zone B cells and memory B cells.350,351 YAP-TEAD interaction or inhibiting TEAD activity, which makes
In addition, among the immune cells that can be regulated by these potential targets interfere with the Hippo pathway.
the Hippo pathway, Treg cells and Th17 cells are worthy of
attention because of their close connection to autoimmune Hippo core kinase inhibition. Hippo core kinases can be manipu-
diseases.352,353 It was reported that Mst1-Mst2 was essential for lated by kinase inhibition or altering protein expression. MST
maintaining the Treg pool, while TAZ contributed to the kinase activity inhibitors are the most common Hippo core kinase
production of Th17 cells and the function of Tregs. Deletion of activity inhibitors in preclinical studies. In particular, XMU-MP-1, an
Mst1-Mst2 led to autoimmune diseases. However, TAZ knockout MST1/2 inhibitor identified by Fan et al.201 has been studied
made the mice resistant to autoimmune encephalomyelitis.354,355 extensively in a variety of diseases. The initial effect of XMU-MP-1

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Table 2. The drugs targeting Hippo pathway in clinical trials

Mechanism Name (sponsor) Phase Indications ClinicalTrials.gov Identifier

TEAD palmitoylation inhibition VT3989 (Vivace Therapeutics) Phase 1 Solid Tumour NCT04665206
Mesothelioma
IK-930 (Ikena Oncology) Phase 1 Solid Tumours NCT05228015
Mesothelioma
Epithelioid Hemangioendothelioma
NF2 Deficiency
YAP1 or TAZ Gene Fusions
YAP antisense oligonucleotide ION537 (Ionis Pharmaceuticals) Phase 1 Advanced solid tumours NCT04659096
Not been disclosed IAG933 (Novartis) Phase 1 Mesothelioma NCT04857372

was reported in liver repair and regeneration. Treatment with XMU- AAV-miR-15a treatment.310 This proven efficacy and unique
MP-1 can ameliorate both chronic and acute liver injury in mouse advantages make genetic inhibitors of YAP/TAZ an exciting
models in vivo.201 Combined with nanotechnology, Liu et al.359 potential development prospect. Most notably, thus far, ION537,
loaded XMU-MP-1 in a novel nanohybrid to optimize efficacy. In an antisense medicine targeting YAP1, has been evaluated in
vivo, the XMU-MP-1-loaded nanohybrid showed a longer inhibitory phase I clinical trials. This is a great breakthrough for the
effect on p-YAP and better efficacy in acute liver failure than the development of a Hippo-targeted drug (NCT04659096).372
free drug. In addition, in cancers such as prostate cancer and breast As awareness of the Hippo pathway continues to improve,
cancer, MST frequently plays a protumorigenic role. It was reported new ways to inhibit YAP/TAZ have been discovered recently.
that XMU-MP-1 may have potential in treating prostate and breast SuperHippo, a designed WWC-derived protein, was shown to
cancer because XMU-MP-1 can inhibit proliferation in a variety of inhibit YAP/TAZ activity by inducing the phosphorylation of
prostate and breast cancer cell lines.360 Moreover, in other mouse LATS1/2 due to the requirement of the WWC protein in the
models, such as autoimmune encephalomyelitis and cardiac activation of LATS1/2.31
hypertrophy, XMU-MP-1 could relieve these conditions.361,362
However, XMU-MP-1 is not the most ideal inhibitor of MSTs Inhibition of TEAD and/or the YAP-TEAD interaction. YAP-TEAD
because of its off-target activity.201 Many other MST inhibitors have interaction inhibitors currently offer the diverse potential to target
been identified. Among them, SBP-3264, an MST1/2 small molecule the Hippo pathway. Liu-Chittenden et al. found that verteporfin
inhibitor that was designed recently, could be used to treat acute (VP) could bind to YAP and thereby disrupt its interaction with
myeloid leukaemia.360,363 In addition to MST inhibitors, Hippo core TEAD.373 In subsequent studies, VP was widely used to treat
kinase inhibitors have not been extensively examined. Kastan various diseases, including cancers,374–378 fibrotic diseases379,380
et al.364 identified a potential inhibitor of LATS that was initially and glaucoma.381 Moreover, as a recognized YAP-TEAD interaction
named TRULI. However, more details, including the crystallo- or YAP inhibitor, VP has been frequently used in studies of Hippo-
graphic information of the binding site and the efficacy of the related mechanisms.382,383 However, similar to other potential
inhibitor in treating certain diseases, require further investigation. Hippo-targeted small molecule inhibitors, VP was shown to have
Experiments to reduce Hippo core components rely on gene off-target and YAP-independent toxic effects.384
knockout/knockdown. The downregulation of multiple Hippo Other widely discussed Hippo-targeted YAP-TEAD inhibitors are
kinases has the potential to treat diseases. For example, it was VGLL4 peptide mimetics. Based on the mechanism by which
reported that knocking down Sav significantly ameliorated heart VGLL4 can bind to TEAD and compete with YAP/TAZ,385,386 VGLL4
failure.365 Consistently, studies in mice with ischaemic heart failure peptide mimetics were designed to disrupt the YAP–TEAD
showed improved heart function after Sav knockdown.301 In partial interaction. Studies of their efficacy are mainly related to cancer
hepatectomy mouse models, siRNA-mediated knockdown of treatment. For example, Super-TDU was designed by Jiao et al. to
MST1/2 efficiently induced liver regeneration.330 treat gastric cancer in mouse models. After Super-TD treatment,
YAP target genes were suppressed, and the tumour was markedly
Inhibition of YAP/TAZ expression/activity. Modulation of YAP/TAZ remitted.44 In another study, Super-TDU was used to treat
protein levels or activity mainly involves two approaches in colorectal cancer. Similarly, tumour growth was significantly
preclinical and clinical studies: pharmacological inhibition and suppressed. Overall, VGLL4 peptide mimetics may be potential
genetic inhibition. CA3 is the representative pharmacological Hippo-targeted cancer drugs.387
inhibitor of YAP expression that was identified through chemical With further exploration of the YAP–TEAD complex structure,
library screening; however, the detailed mechanism has not been the palmitoylation pocket of TEAD has become a new target for
studied thoroughly.366 CA3 treatment reduces the growth of inhibiting the transcriptional activity of YAP–TEAD. Palmitoylation
oesophageal adenocarcinoma and osteosarcoma.366,367 is a kind of protein modification that changes cysteine thiols of the
Genetic inhibition is another commonly used approach to substrate protein to thioesters with a palmitoyl group.388 In TEAD,
decrease the expression of YAP/TAZ. siRNA therapy is an it was previously found that the palmitate chain was inserted into
alternative to small-molecule inhibitors and has more specifi- a hydrophobic pocket of TEAD, and palmitoylation played an
city.368 The efficacy of YAP/TAZ-based siRNA therapy has been important role in the binding between TEAD and YAP/TAZ.389 The
verified in a variety of animal models. D/R@Ang2-Lip+Au, a TEAD transcription factor is very unique in these properties and is
doxorubicin- and YAP-siRNA-loaded cationic liposome, was able to not shared by any other transcription factors that normally are
effectively inhibit glioblastoma.369 In addition, another YAP-siRNA- very difficult to target. In contrast, due to palmitoylation, TEAD is
lipid nanoparticle repressed hepatocellular carcinoma in a mouse rather easy to target. Thus, there have been pharmaceutical efforts
model.370 In addition to cancer treatment, YAP-siRNA was effective to develop TEAD inhibitors. Chloromethyl ketone 2, a derivative of
in treating posterior segment neovascularization-related ocular FA that was identified in 2019, has been proven to disrupt TEAD4
diseases.371 In addition to siRNA, shRNA is another common tool binding to YAP1 by binding to the TEAD4 palmitate pocket. In
for genetic inhibition. Bleomycin-induced pulmonary fibrosis was vitro, the potential for treating glioblastoma has been demon-
attenuated when YAP was downregulated by AAV5-sh-YAP1 and strated.390 Strikingly, three TEAD palmitoylation inhibitors have

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AUTHOR CONTRIBUTIONS 30. Chan, E. H. et al. The Ste20-like kinase Mst2 activates the human large tumor
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K.-L.G. gave valuable and constructive suggestions for the outline and the content of 31. Qi, S. et al. WWC proteins mediate LATS1/2 activation by Hippo kinases and
this paper. T.L. and M.L. developed and revised this paper. All authors have read and imply a tumor suppression strategy. Mol. Cell 82, 1850–1864 (2022).
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to regulate intestinal stem cells in. Drosoph. Dev. Cell 31, 291–304 (2014).
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ADDITIONAL INFORMATION Hippo signaling. Cell Discov. 1, 15038 (2015).
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Competing interests: K.L.G. is a co-founder of and has equity interest in Vivace
2 in the Hippo pathway. Nat. Commun. 6, 8357 (2015).
Therapeutics. Other authors declare that they have no conflict of interest.
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