The Hippo pathway and its correlation with acute kidney injury

Acute kidney injury(AKI) is a significant clinical complication with a substantial impact on morbidity and mortality, for which therapeutic options remain limited. The Hippo signaling pathway is an evolutionarily conserved pathway implicated in cell proliferation, dedifferentiation, and apoptosis via phosphorylation and inactivation of its downstream effectorsYes-associatedprotein(YAP)/transcriptional co-activator with PDZ-binding motif(TAZ). Recent studies have revealed that the Hippo pathway plays a pivotal role in the pathogenesis and repair of AKI. The Hippo pathway can mediate renal dysfunction through modulation of mitochondrial apoptosis under AKI conditions. Transient activation of YAP/TAZ in the acute phase of AKI may benefit renal recovery and regeneration, whereas persistent activation of YAP/TAZ in severe AKI may lead to maladaptive repair and transition to chronic kidney disease. This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.

Mechanism of action of cordycepin in the treatment of hepatocellular carcinoma via regulation of the Hippo signaling pathway

Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.

Hippo pathway-manipulating neutrophil-mimic hybrid nanoparticles for cardiac ischemic injury via modulation of local immunity and cardiac regeneration

The promise of regeneration therapy for restoration of damaged myocardium after cardiac ischemic injury relies on targeted delivery of proliferative molecules into cardiomyocytes whose healing benefits are still limited owing to severe immune microenvironment due to local high concentration of proinflammatory cytokines.Optimal therapeutic strategies are therefore in urgent need to both modulate local immunity and deliver proliferative molecules.Here,we addressed this unmet need by developing neutrophil-mimic nanoparticles NM@miR,fabricated by coating hybrid neutrophil membranes with artificial lipids onto mesoporous silica nanoparticles(MSNs)loaded with microRNA-10b.The hybrid membrane could endow nanoparticles with strong capacity to migrate into infammatory sites and neutralize proinfammatory cytokines and increase the delivery efficiency of microRNA-1Ob into adult mammalian cardiomyocytes(CMs)by fusing with cell membranes and leading to the release of MSNs-miR into cytosol.Upon NM@miR administration,this nanoparticle could home to the injured myocardium,restore the local immunity,and efficiently deliver microRNA-1Ob to cardiomyocytes,which could reduce the activation of Hippo-YAP pathway mediated by excessive cytokines and exert the best proliferative effect of miR-1Ob.This combination therapy could finally improve cardiac function and mitigate ventricular remodeling.Consequently,this work offers a combination strategy of immunity modulation and proliferative molecule delivery to boost cardiac regeneration after injury.

Mechanism of Huatan Sanjie Fang in improving goiter in Graves'disease mice based on the Hippo signaling pathway

Objective:To explore the mechanism of Huatan Sanjie Fang(HTSJ)in regulating goiter in Graves'disease(GD)mice by detecting key factors of the Hippo signaling pathway.Methods:A mouse model of GD was established by injecting Ad-TSHR289 adenovirus into the bilateral quadriceps femoris of female mice.Successful mouse models were then randomly divided into a model group,methimazole(MMI)group,and HTSJ group,and fed with deionized water,MMI(4.5 mg/kg per day),and HTSJ(35.10 g/kg per day),respectively,for 10 weeks.Histopathological changes of the thyroid gland were subsequently observed by hematoxylin-eosin staining.Radioimmunoassay was used to detect serum total thyroxine(T4)and thyrotrophin-receptor antibody(TRAb)levels.The relative expression of mRNA of Mst1,YAP,and TAZ were detected by quantitative real-time polymerase chain reaction,while the protein expression of Mst1,YAP,TAZ,pMst1,and pYAP were detected by western blot.Results:After 10 weeks of drug intervention,goiter and other pathological changes in the HTSJ group significantly improved compared with the model group,and the levels of serum T4 and TRAb significantly decreased(P=.002,P<.001,respectively).Decreased mRNA expression of Mst1,YAP,and TAZ,the key factors of the Hippo signaling transduction pathway,was also observed(P=.002,P=.022,P<.001,respectively).In contrast,protein expression of Mst1(P=.046),pMst1(P=.026),and p YAP(P=.004)increased,while protein expression of YAP and TAZ decreased(P=.041,P<.001,respectively).Conclusion:HTSJ can effectively improve goiter in GD mice through the Hippo signaling pathway.

The Hippo pathway regulates stem cell proliferation,self-renewal,and differentiation

Stem cells and progenitor cells are the cells of origin for multi-cellular organisms and organs.They play key roles during development and their dysregulation gives rise to human diseases such as cancer.The recent de-velopment of induced pluripotent stem cell(iPSC)technology which converts somatic cells to stem-like cells holds great promise for regenerative medicine.Nevertheless,the understanding of proliferation,dif-ferentiation,and self-renewal of stem cells and or-gan-specific progenitor cells is far from clear.Recently,the Hippo pathway was demonstrated to play important roles in these processes.The Hippo pathway is a newly established signaling pathway with critical functions in limiting organ size and suppressing tumorigenesis.This pathway was first found to inhibit cell proliferation and promote apoptosis,therefore regulating cell num-ber and organ size in both Drosophila and mammals.However,in several organs,disturbance of the pathway leads to specific expansion of the progenitor cell com-partment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and dif-ferentiation.In this review,we summarize current ob-servations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ de-velopment and tumorigenesis.

BmSd gene regulates the silkworm wing size by affecting the Hippo pathway

Insect wings are developed from the wing disc during metamorphosis.Bombyx mori,a model lepidopteran insect,loses flight ability after long-term domestication from the wild silkworm,Bombyx mandarina.The mw mutant(ul 1 strain)shows minute wings compared to wild type(e.g.,p50 strain)wings.RNA sequencing analysis previously revealed differential Hippo-pathway-related gene expression between the ull and p50strains.The Hippo pathway is an evolutionarily conserved signaling cascade that controls organ size during development in animals.In this study,the function of BmSd which has been characterized as one of the Hippo-pathway-related genes was analyzed for silkworm wing development.We found that mats,warts,and hippo expression levels were higher in u11 compared to p50 wing discs.BmSd(scalloped)expression,which encodes a prominent transcriptional partner to Yorkie(Yki),gradually decreased during the wandering stage in ull,but exhibited the opposite expression pattern in p50.When BmSd was knocked down by small interfering RNA during the wandering stage in the p50 strain,57.9%of the individuals showed minute wings.Additionally,ex,kibras and wingless expression levels decreased in the BmSd knockdown mutant.Further,BmSd deletion mediated by clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 induced 50%of individuals with minute wings,a phenotype similar to the mw mutant.This result demonstrates that BmSd plays pivotal roles in silkworm wing development.Our results show that the Hippo signaling pathway participates and plays crucial roles in the regulation of silkworm wing development,and our findings provide a basis for further research on B.mori wing development.

Regulation of ferroptosis in cancer cells by YAP/TAZ and Hippo pathways:The therapeutic implications

Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.

Deciphering tumor-suppressor signaling in flies:Genetic link between Scribble/Dlg/Lgl and the Hippo pathways

Loss of apico-basal polarity is one of the crucial factors that drives epithelial tumor progression, scribbleldiscs largellethal giant larvae （scrib/dlg/lgl）, a group of apico-basal polarity genes, were initially identified as members of ＂neoplastic＂ tumor-suppressors in flies. The components of the Hippo signaling pathway, which is crucial for organ size control and cancer development, were also identified through Drosophila genetic screens as members of ＂hyperplastic＂ tumor-suppressors. Accumulating evidence in recent studies implies that these two tumor-suppressor signaling pathways are not mutually exclusive but rather cooperatively act to give rise to highly malignant tumors. The interaction of these tumor-suppressor pathways could include deregulations of actin cytoskeleton, cell-cell contact, and apical-domain size of

Shaggy regulates tissue growth through Hippo pathway in Drosophila

The evolutionarily conserved Hippo pathway coordinates cell proliferation,differentiation and apoptosis to regulate organ growth and tumorigenesis.Hippo signaling activity is tightly controlled by various upstream signals including growth factors and cell polarity,but the full extent to which the pathway is regulated during development remains to be resolved.Here,we report the identification of Shaggy,the homolog of mammalian Gsk3β,as a novel regulator of the Hippo pathway in Drosophila.Our results show that Shaggy promotes the expression of Hippo target genes in a manner that is dependent on its kinase activity.Loss of Shaggy leads to Yorkie inhibition and downregulation of Hippo pathway target genes.Mechanistically,Shaggy acts upstream of the Hippo pathway and negatively regulates the abundance of the FERM domain containing adaptor protein Expanded.Our results reveal that Shaggy is functionally required for Crumbs/Slmb-mediated downregulation of Expanded in vivo,providing a potential molecular link between cellular architecture and the Hippo signaling pathway.

Scutellarin induces apoptosis of colorectal cancer HCT116 cells via Hippo signaling pathway

OBJECTIVE To investigate the effect of scutellarin on the apoptosis of human colorectal cancer cells via the Hippo signaling pathway in vitro.METHODS MTT colorimetric method was used to detect the influence of scutellarin on the survival rate of HCT116 cells.And the effect of scutellarin at various concentrations on cell morphology was observed by microscopy.Cell scratch experiment was used to detect the influence of scutellarin on the migration of HCT116 cells.Hoechst33342/PI double staining method was used to detect the effect of scutellarin on the apoptosis of HCT116 cells.Western blotting method was used to assess the action of scutellarin on the expressions of Hippo signaling pathway-related proteins Mst1,Lats1,YAP1,p-YAP(Ser127),TAZ,and its downstream effector proteins c-Myc and cyclin D1,as well as apoptosis-related proteins Bcl-2 and Bax in HCT116 cells.RESULTS Scutellarin significantly affected the morphology of HCT116 cells and reduced the survival rate of HCT116 cells.Hoechst33342/PI double staining showed that scutellarin effectively induced the apoptosis of HCT116 cells.Western blotting analysis showed that the expression levels of Hippo signaling pathway-related proteins Mst1,Lats1,YAP1,TAZ and its downstream effector proteins c-Myc,cyclin D1 were down-regulated in a concentration-dependent manner by scutellarin,and the expression of p-YAP(ser127)was up-regulated.Moreover,scutellarin substantially lessened the expression level of apoptosis-related protein Bcl-2,and promoted the protein level of Bax.CONCLUSION Scutellarin may inhibit the proliferation and migration of HCT116 cells,while induce its apoptosis,potentially by activation of Hippo signaling pathway.

Salsolinol as an RNA m~6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy

Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.

Hippo signaling:bridging the gap between cancer and neurodegenerative disorders

During development,regulation of organ size requires a balance between cell proliferation,growth and cell death.Dysregulation of these fundamental processes can cause a variety of diseases.Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders.Many signaling pathways known-to-date have a role in growth regulation.Among them,evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development.Neurodegeneration,a complex process of progressive death of neuronal population,results in fatal disorders with no available cure to date.During normal development,cell death is required for sculpting of an organ.However,aberrant cell death in neuronal cell population can result in neurodegenerative disorders.Hippo pathway has gathered major attention for its role in growth regulation and cancer,however,other functions like its role in neurodegeneration are also emerging rapidly.This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway.Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.

Heat exposure promotes apoptosis and pyroptosis in Sertoli cells

Heat stress is an important influence on the male reproductive organs.Therefore,the effects of heat stress on genes or pathways related to the reproductive system of male mice were experimentally explored in this paper to further determine the effects of heat stimulation on mammals.Herein,models of heat-exposed mouse testicular tissue and heatexcited cells were successfully established.Many scorched vesicles were found after heat excitation of testis supporting cells,testicular mesenchymal(TM4)cells.Western blot,in situ terminal deoxynucleotide transferase dUTP Nick end labeling(TUNEL)and transmission electron microscopy showed that membrane rupture,mitochondrial damage and autophagic vesicles occurred in TM4 cells after thermal excitation.The N-segment fragment of the associated protein shear was increased,and the TUNEL result was positive.In conclusion,thermal excitation induced apoptosis and scorch death in TM4 cells.Thus,the Hippo pathway and apoptosis-related pathway were significantly enriched after heat stimulation in mouse testis,and the scorch death effect in TM4 cells was induced by heat excitation.

The roles and regulation of Yes-associated protein 1 in stem cells

Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of YAP1 in mediating stem cell fate decisions are discussed,including cell proliferation,differentiation,and apoptosis.In general,YAP1 promotes the proliferation and differentiation of stem cells,including embryonic stem cells and adult stem cells.It inhibits apoptosis by binding to the transcription factors,e.g.,transcriptional enhanced associate domain(TEAD),Smad,runt-related transcription factor 1/2,p73,p63,and Erb84,to maintain tissue homeostasis.The translocalization of YAP1 in cellular nuclei and the phosphorylation in the cytoplasm work as important and unusual events for the activation of YAP1.Moreover,YAP1 serves as the crosstalk for the Hippo pathway and other signaling pathways,including the Wnt and Notch pathways.It is highlighted in this review that YAP1 is an essential regulator for stem cells that have significant applications in regenerative medicine and reproductive medicine.

The Hippo Tumor Suppressor Pathway(YAP/TAZ/TEAD/MST/LATS)and EGFR-RAS-RAF-MEK in cancer metastasis

Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polarity,transduction,and DNA damage)and limited by growth factors or mitogens associated with EGF and LPA.The major pathway consists of the central kinase of Ste20 MAPK(Saccharomyces cerevisiae),Hpo(Drosophila melanogaster)or MST kinases(mammalian)that activates the mammalian AGC kinase dmWts or LATS effector(MST and LATS).YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation(TEA domain family,TEAD1-4),stem cells(Oct4 mononuclear factor and SMAD-related TGFb effector),differentiation(RUNX1),and Cell cycle/apoptosis control(p53,p63,and p73 family members).This is due to the diverse roles of YAP and may limit tumor progression and establishment.TEAD also coordinates various signal transduction pathways such as Hippo,WNT,TGFb and EGFR,and effects on lack of regulation of TEAD cancerous genes,such as KRAS,BRAF,LKB1,NF2 and MYC,which play essential roles in tumor progression,metastasis,cancer metabolism,immunity,and drug resistance.However,RAS signaling is a pivotal factor in the inactivation of Hippo,which controls EGFR-RAS-RAF-MEK-ERKmediated interaction of Hippo signaling.Thus,the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.

YAP activates pancreatic stellate cells and enhances pancreatic fibrosis

Background:Pancreatic stellate cells(PSCs)foster the progression of pancreatic adenocarcinoma and chronic pancreatitis(CP)by producing a dense fibrotic stroma.However,the incomplete knowledge of PSCs biology hampers the exploration of antifibrotic therapies.Here,we explored the role of the Hippo pathway in the context of PSCs activation and experimental CP.Methods:CP model was created in rats with the tail vein injection of dibutyltin dichloride(DBTC).The expression of Yes-associated protein(YAP)in CP tissue was assessed.Primary and immortalized rats PSCs were treated with the YAP-inhibitor verteporfin.Furthermore,YAP siRNA was employed.Subsequently,DNA synthesis,cell survival,levels ofα-smooth muscle actin(α-SMA)protein,presence of lipid droplets and PSCs gene expression were evaluated.Upstream regulators of YAP signaling were studied by reporter gene assays.Results:In DBTC-induced CP,pronounced expression of YAP in areas of tubular structures and periduc-tal fibrosis was observed.Verteporfin diminished DNA replication in PSCs in a dose-dependent fash-ion.Knockdown of YAP reduced cell proliferation.Primary cultures of PSCs were characterized by a de-crease of lipid droplets and increased synthesis ofα-SMA protein.Both processes were not affected by verteporfin.At the non-cytotoxic concentration of 100 nmol/L,verteporfin significantly reduced mRNA levels of transforming growth factor-β1(Tgf-β1)and Ccn family member 1(Ccn1).YAP signaling was acti-vated by TGF-β1,but repressed by interferon-γ.Conclusions:Activated YAP enhanced PSCs proliferation.The antifibrotic potential of Hippo pathway in-hibitors warrants further investigation.

The role of YAP in the control of the metastatic potential of oral cancer

The Yes-associated protein(YAP)is a downstream effector of the Hippo pathway and acts as a key transcription co-factor to regulate cell migration,proliferation,and survival.The Hippo pathway is evolutionarily conserved and controls tissue growth and organ size.Dysregulation and heterogeneity of this pathway are found in cancers,including oral squamous cell carcinoma(OSCC),leading to overexpression of YAP and its regulated proliferation machinery.The activity of YAP is associated with its nuclear expression and is negatively regulated by the Hippo kinase-mediated phosphorylation resulting in an induction of its cytoplasmic translocation.This review focuses on the role of YAP in OSCC in the context of cancer metastatic potential and highlights the latestfindings about the heterogeneity of YAP expression and its nuclear transcription activity in oral cancer cell lines.The review also discusses the potential target of YAP in oral cancer therapy and the recentfinding of the unprecedented role of the desmosomal cadherin desmoglein-3(DSG3)in regulating Hippo-YAP signaling.

Regulation of the Hippo signaling pathway by deubiquitinating enzymes in cancer

Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deubiquitinases(DUBs)are a family of proteases that act upon many proteins.While ubiquitinases add ubiquitin and target proteins for degradation,DUBs act by removing ubiquitin(Ub)moieties.Changes in ubiquitin chain topology results in the stabilization of proteins,membrane trafficking,and the alteration of cellular localization.While the roles of these proteins have been well established in a cancer setting,their convergence in cancer is still under investigation.In this review,we discuss the roles that DUBs play in the regulation of the Hippo signaling pathway for homeostasis and disease.

Role of Hippo signaling in regulating immunity

The Hippo signaling pathway has been established as a key regulator of organ size control,tumor suppression,and tissue regeneration in multiple organisms.Recently,emerging evidence has indicated that Hippo signaling might play an important role in regulating the immune system in both Drosophila and mammals.In particular,patients bearing a loss-of-function mutation of MST1 are reported to have an autosomal recessive primary immunodeficiency syndrome.MST1/2 kinases,the mammalian orthologs of Drosophila Hippo,may activate the non-canonical Hippo signaling pathway via MOB1A/B and/or NDR1/2 or cross-talk with other essential signaling pathways to regulate both innate and adaptive immunity.In this review,we present and discuss recent findings of cellular mechanisms/functions of Hippo signaling in the innate immunity in Drosophila and in mammals,T cell immunity,as well as the implications of Hippo signaling for tumor immunity.

Hippo signaling and epithelial cell plasticity in mammalian liver development, homeostasis, injury and disease

A traditional view of cellular differentiation is unidirectional: progenitor cells adopt specific fates in response to environmental cues resulting in deployment of cell-specific gene expression programs and acquisition of unique differentiated cellular properties such as production of structural and functional proteins that define individual cell types. In both development and in tissue repair stem and progenitor cells are thought to both self-renew to maintain the pool of precursors and to expand to give rise to transient amplifying and differentiated cell types. Recently, however, it has become appreciated that differentiated cell types can be reprogrammed to adopt progenitor and stem cell properties. In the case of epithelial cells in the mammalian liver, hepatocytes and biliary epithelial cells there is a significant degree of plasticity between these lineages that has been implicated in mechanisms of tissue repair and in liver pathologies such as cancer. Recent studies have highlighted the role of Hippo signaling, an emerging growth control and tumor suppressor pathway, in regulating epithelial cell plasticity in the mammalian liver and in this review, the role of cellular plasticity and Hippo signaling in regulating normal and abnormal tissue responses in the mammalian liver will be discussed.