YAP1 is an oncogene (17) and its overexpression can lead to the development of liver cancer (18-21), including HCC (22-32), CC (33,34) and hepatoblastoma (HB) (35,36). Elevated nuclear YAP1 expression is observed in HCC (37). Enhanced YAP1 activity promoted the proliferation of HCC (38,39). High YAP1 expression drives HCC proliferation (40-43). The overexpression of YAP1, combined with the knockdown of serine/arginine-rich splicing factor 1 (also known as SF2) further promotes tumor growth (44). YAP1 promotes cancer progression (45). Furthermore, YAP1/TAZ may play an early role in HCC progression (46). Studies have also shown that YAP1 and TAZ are highly expressed and activated in HCC, cholangiocarcinoma (CCA) and combined HCC-CCA (47,48). Of note, studies have also shown that YAP1 and TAZ eliminate tumor cells through cellular competition mechanisms. Normal hepatocytes surrounding liver tumors show activation of YAP1 and TAZ, and the absence of YAP1 and TAZ in these surrounding hepatocyte tumors accelerates tumor growth (49). Stathmin 1 (also known as oncoprotein-18), is a cytoplasmic phosphorylated protein that controls cell microtubule dynamics. Its upregulation promotes HCC development by activating the YAP1 signaling pathway (50). Glypican-3 (GPC3) is a protein that plays a crucial role in HCC development and progression. Inhibition of GPC3 inhibits the proliferation of HCC cells and induces apoptosis by decreasing YAP1 (51). Rac GTPase-activating protein 1 (RACGAP1) is a cytokinetic regulatory protein highly expressed in various cancers. RACGAP1 promotes HCC proliferation by decreasing the activation of the Hippo and YAP1 pathways (52). RNA binding motif protein 3, part of a family of RNA binding proteins rich in glycine, promotes HCC cell proliferation by upregulating YAP1 expression (53). The decrease in succinate dehydrogenase enzyme (SDH) is associated with increased succinate level and poor prognosis in patients with HCC. The decrease of SDH subunits A and B was reported to promote HCC proliferation by preventing the proteasome degradation of YAP1/TAZ (54).

Overexpression of YAP1 promotes HCC migration and invasion (55). Contrarily, YAP1 knockdown inhibits the invasion of HCC cells by modulating the characteristics of epithelial-mesenchymal transition (EMT) (56). YAP1 enhances HCC metastasis and mobilization by restricting the JNK/BCL2 interacting protein 3/ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting/calcium/calmodulin dependent protein kinase II pathway, which mediates the activation of cofilin/F-actin/lamellipodium axis (57). Zinc finger protein 191 inhibits the activation of YAP1 and metastasis of HCC by upregulating DLG1 (58). Integrin-αV is a TAZ target gene and its inhibition reduces nuclear YAP1/TAZ protein levels and suppresses HCC migration (59). The interaction of α-catenin with YAP1/FoxM1/TEAD induces centrosomal protein 55 to promote HCC cell migration (60). Septin 6 promotes F-actin formation, upregulates YAP1 expression and enhances its nuclear translocation, thereby driving HCC progression (61).

YAP1 promotes sorafenib resistance by upregulating survivin expression in HCC cells (62). Silencing YAP1 and insulin-like growth factor 2 mRNA binding protein 3 restores transforming growth factor-β (TGF-β) signaling, suppresses pluripotent genes and tumorigenesis and eliminates chemotherapy resistance in tumor-initiating stem-like cells (TICs) (63). Dual downregulation of TAZ/YAP1 reduces chemotherapy resistance and tumorigenicity (64,65). Mex-3 RNA binding family member A (MEX3A), an RNA-binding protein, has been implicated in cancer development (66). MEX3A may promote HCC progression and hinder sorafenib sensitivity by inactivating the Hippo signaling pathway (67). Claudin 6 (CLDN6) is highly expressed in a variety of cancers (68). Overexpression of CLDN6 increases YAP1 and TAZ abundance, making sorafenib treatment less effective (69).

Tumor development is also a result of metabolic reprogramming (70). Studies have indicated that YAP1 can reprogram cellular metabolism (71). Glycogen accumulation is a key oncogenic event in the malignant transformation of the liver. Deficiency in glucose-6-phosphatase or liver glycogen phosphorylase leads to glycogen storage disease, liver enlargement and tumorigenesis in a YAP1-dependent manner (72). Enolase 1 (ENO1), a glycolytic enzyme, shows abnormal activation in the ENO1/YAP1/PLCB pathway in clinical HCC samples (73). High mobility group box 1 (HMGB1) is a chromosomal protein that promotes HCC development by inducing YAP1/HIF1α-dependent aerobic glycolysis (74). In addition, Hmgb1 accelerates HCC by activating YAP1 in Hippo signaling-deficient mice (75). YAP1 reprograms glutamine metabolism and YAP1 activation stimulates nucleotide biosynthesis by enhancing the expression and activity of glutamine synthetase (GLUL). Genetic or pharmacological inhibition of GLUL inhibits Yap1-induced hepatomegaly and HCC development (76). YAP1/TAZ regulates amino acid metabolism by upregulating the expression of amino acid transporters solute carrier family 38 member 1 (SLC38A1) and SLC7A5, which are critical for tumor cell formation, growth and progression (77). Bile acids (BAs) act as signaling molecules and tumor promoters by driving YAP1 activation. Studies have shown that the ability of BAs to activate YAP1 is concentration-dependent (78). Loss of the nuclear receptors nuclear receptor subfamily 1 group H member 4 and small heterodimer partner leads to YAP1 activation in mice, resulting in severe deficiencies in BA homeostasis liver enlargement and liver tumorigenesis (78). BAs act as an upstream regulator of YAP1 through a pathway dependent on the induction of scaffold protein IQ motif-containing GTPase-activating protein 1 (IQGAP1) (78). IQGAP1 is a driver of HCC tumors by enhancing YAP1 (79). Cholesterol metabolism has an important role in maintaining membrane integrity and combating diseases such as obesity and cancer. COP9 signalosome subunit 6 antagonizes speckle-type POZ protein ubiquitin ligase to stabilize hydroxymethylglutaryl-CoA synthase 1, thereby activating YAP1 and promoting tumor growth (80).

Tumor-associated macrophages (TAM) are the most abundant immune-associated stromal cells in the tumor microenvironment. TAM exhibit great phenotypic heterogeneity and have various functions, such as promoting tumor growth, metastasis and angiogenesis (81). Previous studies have shown that M2-type macrophages in HCC induce cell proliferation and angiogenesis (82). In addition, M2-type macrophage-derived extracellular vesicles promote T-cell exhaustion in HCC by activating the YAP1/β-catenin pathway (83). The interaction between ETS variant transcription factor 4 and YAP1 promotes the growth of HCC, resulting in an increase in macrophages and a decrease in T-cell and natural killer-cell infiltration in the tumor (84). Nogo-B promotes HCC progression by enhancing YAP1/TAZ-mediated polarization of M2-type TAM (85). IL-6 secreted by YAP1-activated HCC cells may induce TAM recruitment (86). The activation of YAP1 is essential for the recruitment of M2-type macrophages by TICs in the liver and TAM protect TIC from immune clearance (87). RACGAP1 promotes HCC development through immunosuppression mediated by YAP1activation (88). In patients with HCC, YAP1 overexpression in peripheral blood T cells is associated with an increased percentage of T-regulatory cells in peripheral blood mononuclear cells, indicating a poor prognosis (31).

YAP1 activity is associated with the autophagy process in HCC (89,90). In HCC, activation of YAP1 expression promotes autophagy, while downregulation of YAP1 expression inhibits autophagy (91,92). A previous studies by our group found that YAP1 and autophagy produced positive feedback in HCC cells (93). Furthermore, inhibition of YAP1 reduces autophagy activity and improves the efficacy of anti-programmed cell death 1 (PD-1) treatment in HCC (93). It was also reported that chaperone-mediated autophagy impairment leads to YAP1 and IL-6 cytokine family signal transducer degradation, promoting the proliferation and migration of both normal and HCC cells (89). In HCC stem cells, fluid shear stress induces cell migration through the ras homolog family member A-YAP1 autophagy pathway (94).

CIN can induce polyploidy and aneuploidy of cells, which are hallmarks of cancer. The increase in CIN, polyploid and aneuploid is closely related to the occurrence and development of HCC (95). Studies have shown that YAP1 induces forkhead box (FOX)M1 to drive the expression of CIN-related genes and promote the development of HCC (96). YAP1 promotes diploid-polyploid transformation and polyploid cell growth through the protein kinase B (Akt)-S-phase kinase associated protein 2 (Skp2) axis. YAP1 strongly induces acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 through Akt signaling. Acetylated Skp2 is localized only to the cytoplasm, leading to excessive accumulation of the cyclin-dependent kinase inhibitor p27, resulting in mitotic arrest and cell polyploidy. In addition, the pro-apoptotic factor FOXO1/3 is over-degraded by acetylated Skp2, leading to polyploid cell division, genomic instability and tumorigenesis (97). Leucine rich pentatricopeptide repeat containing inhibits genomic instability and HCC by maintaining Yap1-p27-mediated cell ploidy and p62-histone deacetylase 6-controlled autophagy maturation (98).

Numerous signaling pathways, including Wnt, mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K) and Notch, have been shown to regulate YAP1/TAZ activity in HCC through crosstalk with the Hippo signaling pathway (2). The crosstalk of Hippo signaling pathways with other signaling pathways to regulate YAP1 is illustrated in Fig. 3. Activation of Wnt/β-catenin signaling inhibits HCC formation by disrupting the positive feedback loop between YAP1/TAZ and Notch signaling (124). Overexpression of R-spondin 2 activates both typical Wnt/β-catenin and Hippo/YAP1 signaling, promoting HCC formation (125). Various mutations in β-catenin combined with YAP1 drive HB development (126). The upregulation of YAP1 and β-catenin expression is observed in HCC (127,128). The role of MYC and β-catenin in liver tumorigenesis are dependent on Yap1/WW domain containing transcription regulator 1 activity (129). Frizzled 10 (FZD10) enhances the self-renewal, tumorigenicity and metastasis of liver cancer stem cells (CSCs) by activating β-catenin and YAP1 (130). Tribbles homolog 2 is a direct target of Wnt/T-cell factor in HCC, promoting the stabilization and nuclear localization of YAP1 and contributing to the development of fibrosis-associated HCC (131).

The MAPK signaling pathway has a key role in numerous human diseases, including cancer. It is activated in numerous tumors, with various components identified as oncogenes (132). A previous study by our group found that tumor cells promoted phosphorylated (p-)ERK and expression of YAP1 through cell surface PD-1/programmed death ligand-1 (PD-L1) interactions. Therefore, blocking the binding of PD-1 and PD-L1 inhibited the p-ERK/YAP1 pathway and reduced tumor cell proliferation (133). Studies have also shown that MAPK kinase 1 interacts with YAP1 to promote YAP1 expression, which supports the proliferation and phenotypic transformation of hepatoma cells (134). In lenvatinib-resistant HCC cells, the ERK/YAP1 signaling pathway mediates the upregulation of cyclin-dependent kinase 6 (135).

Simultaneous activation of PI3K and YAP1 pathways often occurs in HCC and their combined inhibition is unfavorable to HCC growth (136). PI3K/AKT signaling regulates CD166 (also known as Alcam), playing an anti-apoptotic role in HCC via YAP1 (137). Standard CD44 (CD44S) positively regulates the expression of YAP1 and its target genes in HCC cells through the PI3K/AKT pathway (138). The mTOR complex 1 (mTORC1) pathway is a major oncogenic pathway acting downstream of PI3K and AKT (139). The mTORC1/AT-rich interaction domain 1A axis promotes carcinogenic chromatin remodeling and YAP1-dependent transcription, thus promoting HCC development (140).

EMT is important for HCC metastasis (141,142). FZD2 promotes the progression of EMT and HCC by activating the Hippo/YAP1 pathway (143). Programmed cell death 10 activates YAP1 through interaction with protein phosphatase 2A (PP2Ac), promoting the progression of EMT and HCC (144). Overexpression of retinal dehydrogenase 5 activates the Hippo/YAP1 signaling pathway, promotes YAP1 nuclear translocation and alleviates metastasis of HCC (145). Snail family transcriptional repressor 1 is a primary regulator of EMT and its overexpression promotes the expression of YAP1 (146).

In addition, transcriptional regulator YAP1 has been found to upregulate Notch ligand Jagged-1 (Jag-1), thereby activating Notch signaling in HCC cells and mouse hepatocytes. In human HCC and colorectal tumor samples, the activity of YAP1-dependent Jag-1 and Notch was observed to correlate with patient survival time. These results show that YAP1 and Notch inhibitors can be used as therapeutics for gastrointestinal cancers (147).

The ECM is a major component of tumors, playing a vital role in mechanical support, microenvironment regulation and as a source of signaling molecules (148). The Hippo pathway effector molecules YAP1 and TAZ function as nuclear sensors for mechanical signals in response to ECM signals. The ECM proteoglycan Agrin promotes tumorigenesis by activating YAP1 (149). Collagens, a key component of ECM, play a significant role as well. Collagen I-discoidin domain receptor 1 signaling inhibits the Hippo pathway by promoting the recruitment of protein phosphatase 2 scaffold subunit Aα to MST1, which activates YAP1 and enhances the stem cell properties of HCC (150).

The EGFR signaling pathway and the Hippo signaling pathway play important roles in the carcinogenesis of HCC (151). Studies have shown that the EGFR/PI3K-phosphoinositide-dependent kinase 1 pathway activates YAP1 signaling in HCC. In addition, activated EGFR signaling can also promote the growth of HCC cells in a YAP1-independent manner (151).

TNF receptor II (TNFR2) is required for TNF-α-induced YAP1 activation during malignant transformation of hepatic progenitor cells (HPC) and liver tumorigenesis. In HPC-like cells that drive HCC, the TNFR2/heterogeneous nuclear ribonucleoprotein K/YAP1 signal is activated and associated with poorer prognosis (152).

The cyclic adenosine monophosphate (cAMP) signaling pathway plays a crucial role in cancer development (153). Phosphodiesterase 4D, a major component of cAMP hydrolysis in many cell types, was observed to form a complex with YAP1 to promote HCC progression (154).

The hepatocyte growth factor/cellular-mesenchymal epithelial transition factor (c-MET) signaling pathway is important for promoting HCC growth, angiogenesis and metastasis (155). Overexpression of SIX homeobox 4 promoted the expression of YAP1 and c-MET, thereby enhancing the invasion and metastasis of HCC (156).

The upstream components of the Hippo pathway appear to be human tumor suppressors. Studies have shown that overexpression of MST1 promotes the phosphorylation of YAP1 (Ser127), inhibits cell proliferation and induces cell apoptosis (157). Combined Mst1/2 deficiency results in loss of inhibitory Ser127 phosphorylation of YAP1, massive overgrowth and HCC (158). Studies have shown that serine/threonine protein kinase 25 enhances YAP1 activation through the regulation of MST1/2 (159). α2β1 integrin binds to the collagen ECM, inhibits MST1 kinase phosphorylation and activates YAP1 to promote cancer (160). Knockdown of MST1 or overexpression of YAP1 reverses tripartite motif containing 21 knockdown-induced HCC growth and chemotherapy-sensitive impairment (161). SIRT7 inhibits MST1 transcription by binding to its promoter and inducing H3K18 deacetylation of the promoter region. High SIRT7 expression is associated with increased YAP1 expression and nuclear localization (162). Striatin 3 inhibits the Hippo pathway, promoting YAP1 nuclear translocation (163). As an inhibitor of YAP1, LATS1 is decreased via RNA interference-mediated downregulation of YAP1 (164). Inhibition of LATS2-mediated dephosphorylation increases the YAP1/TEAD2 association, leading to YAP1/TEAD2 transcriptional activation, as well as upregulated invasion of HCC cells (165). DND microRNA-mediated repression inhibitor 1 promotes LATS2 and phosphorylated YAP1 levels, inhibiting the EMT of HCC (166). TGF-β1 increases the phosphorylation of LATS1 and YAP1, inhibiting HCC growth (167). Overexpression of WW and C2 domain containing 2 inhibits the invasion and metastasis of HCC cells by activating LATS1/2 and phosphorylating YAP1 (168). Loss of PDZ and LIM domain protein 1 leads to dephosphorylation of LATS1 and activation of YAP1, promoting HCC metastasis (169). α-actinin 1 reduced LATS1 and YAP1 phosphorylation and promoted HCC cell proliferation through interaction with MOB1 (170). Highly expressed LIM domain only 3 inhibits the Hippo signaling pathway by interacting with LATS1, promoting the invasion and metastasis of HCC cells (171). The diacylglycerol lipase α/2-arachidonoylglycerol axis significantly inhibits LATS1 and YAP1 phosphorylation, promotes YAP1 nuclear translocation and activity, and induces HCC resistance (172). SAV1 is required for the activation of MST1 and subsequent LATS1/2, and SAV1 knockout leads to the development of HCC (173). Studies have shown that low levels of YAP1 phosphorylation can still be observed in the case of SAV1 knockout. Furthermore, almost all liver cancers caused by specific SAV1 knockout in the liver were mixed liver cancers (174). Angiomotin (AMOT), another regulator of YAP1 in the Hippo pathway, forms a typical Hippo core complex with MST and LATS (175). Studies have shown that AMOT acts as a YAP1 stimulator at high glucose levels and as a YAP1 inhibitor at normal glucose levels (176). LIM domain protein Ajuba regulates YAP1 signaling and is associated with tumorigenesis. Depletion of Ajuba led to increased YAP1 expression in HCC cells, promoting their growth (177). Neurofibromin 2 (NF2) is a tumor suppressor gene. NF2 induces LATS1/2 kinase, which inhibits YAP1/TAZ (178). In the absence of Nf2, Amot promotes nuclear entry and transcriptional activity of Yap1 and is required for liver tumorigenesis (179). Together, these studies suggest that the Hippo-YAP1 signaling pathway is involved in the development of HCC. The dysregulation of Hippo signaling pathway components is frequently observed in HCC.

Although the complete range of downstream targets of YAP1 has yet to be fully elucidated, numerous identified targets are linked to cell growth and survival. In addition, TEAD is essential for the oncogenic function of YAP1/TAZ, thus disrupting the interaction between TEAD and YAP1/TAZ can inhibit YAP1 activity. Silencing TEAD4 in the TEAD gene persistently inhibited tumor growth in HB cell lines and decreased the expression of YAP1 target genes (180). TEAD4 was found to mitigate TGF-β signaling and HCC progression independently of YAP1 (181). Overexpression of hepatocyte nuclear factor 4α significantly impaired the proliferation of YAP1-TEAD-induced HCC cells (182). Targeting downstream effectors of YAP1 could be a potential strategy to inhibit its oncogenic properties. The AXL receptor tyrosine kinase (AXL), a downstream target of YAP1, is involved in cell invasion and metastasis (183). It has been demonstrated that RNA interference-mediated downregulation of AXL expression reduces the proliferation and invasion capabilities of YAP1-expressing HCC cell lines (184). CTGF, a multifunctional signal regulator, promotes cancer occurrence, progression and metastasis by regulating cell proliferation, migration, invasion and drug resistance (185). Sphingosine-1-phosphate (S1P) has been shown to stimulate cell proliferation through YAP1 activation and upregulation of CTGF expression mediated by S1P receptor 2 (186). Overexpression of TNF-α-induced protein 8 (TNFAIP8) increases the nuclear localization and stability of YAP1, upregulates CTGF and promotes HCC progression (187). Furthermore, the loss of CYR61 enhances TGF-β-or YAP1-mediated growth and migration of HCC cells (188). Amphiregulin (AREG), another downstream target of YAP1, has been shown to play a crucial role in inhibiting HCC by inactivating YAP1 (189). NUAK family SNF1-like kinase 2 (NUAK2), also known as sucrose nonfermenting-like kinase, is a member of the AMPK protein kinase family and a direct downstream target of YAP1 (190). Pharmacological inactivation of NUAK2 inhibits YAP1-dependent cancer cell proliferation and liver overgrowth (191). These findings suggest that targeting the downstream effectors of YAP1, such as AXL, CTGF, TNFAIP8, CYR61, AREG and NUAK2, may be an effective strategy for inhibiting YAP1-mediated oncogenesis.

Given the critical role of YAP1 in cancer development, the existing small molecule compounds targeting YAP1 and their mechanisms of action were summarized (Table I). A previous study by our group demonstrated that YAP1 blocked the immunosuppressive microenvironment, thereby enhancing the efficacy of HCC chemotherapy. For instance, cisplatin promotes PD-L1 expression and induces immune tolerance through YAP1 in the HCC microenvironment (192). Verteporfin, a photodynamic drug approved for treating macular degeneration, has shown promising preclinical antitumor effects by inhibiting the YAP1/TAZ pathway (193). In addition, verteporfin exhibited antitumor effects in both intrahepatic and extrahepatic CCA and enhanced tumor growth inhibition when combined with anti-PD-1 (194). Verteporfin significantly improved the efficacy of transcatheter arterial chemoembolization in the treatment of transplanted HCC by inhibiting the Hippo/YAP1 signaling pathway (195). Statins, widely used for treating dyslipidemia and preventing cardiovascular diseases, were found to be associated with a reduced incidence of HCC (196). Statins treatment resulted in the extrusion of YAP1 protein from the nucleus to the cytoplasm (197). The synergistic effect of fibroblast growth factor receptor 4 and EZH2 inhibitors induced the apoptosis of HCC cells by inhibiting YAP1 (198). The compound 12-O-tetradecanoylphorbol-13-acetate, a known carcinogen in rodent skin (199), inhibited YAP1 and HCC cells through AMOT (200). Talazoparib, a potent poly(ADP-ribose) polymerase 1 inhibitor used for treating patients with breast cancer with BRCA1 DNA repair associated (BRCA1) or BRCA2 mutations (201), induced the expression of the tumor suppressor long non-coding RNA polo-like kinase 4, which inhibited HCC cell viability and growth by inactivating YAP1 and inducing cell senescence (202). Dichloroacetate, used for treating mitochondrial genetic diseases and lactic acid poisoning (203), reduced the stemness of HCC cells by promoting the cytoplasmic translocation of YAP1 (204). Fingolimod, a Food and Drug Administration-approved immunomodulator for multiple sclerosis (205), inhibited HCC proliferation by downregulating YAP1 expression (206). Metformin, a first-line treatment for type 2 diabetes, exhibited promising anti-tumor effects by directly inhibiting LATS1/2, activating MST1/2 and phosphorylating YAP1, thereby inhibiting HCC progression (207). Furthermore, metformin increased the sensitivity to chemotherapeutic agents by inhibiting YAP1 in HCC (208). Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor used for treating pulmonary hypertension and erectile dysfunction (209), reduced YAP1/TAZ levels by targeting the PDE5/PKG/Hippo/YAP1/TAZ axis in HCC (210). Vincristine sulfate, a common chemotherapy drug, inhibited YAP1 transcriptional activity and cell proliferation when the tumor supernatant was briefly treated with the drug in vitro (211).

Various studies have shown that natural products play an important role in HCC. Artemisinin and its derivative dihydroartemisinin (DHA) have been found to inhibit HCC (212). Artemisinin inhibits the growth, migration and invasion of HCC by targeting cell bioenergetics and the Hippo/YAP1 signaling pathway (213). Our research group has been studying the anti-HCC mechanism of DHA and found that DHA reduced lipid droplet deposition by YAP1, thereby enhancing the anti-PD-1 effect (214). In addition, DHA inhibited the Warburg effect in HCC via the YAP1/solute carrier family 2 member 1 pathway (215). The present study also showed that DHA increased FXR expression decreased YAP1, and inhibited BA metabolism (216). A previous study by our group found that YAP1 was positively correlated with IL-18, and DHA was effective against HCC by inhibiting both YAP1 and IL-18 (217). Furthermore, DHA disrupted the tumor immunosuppressive microenvironment by inhibiting YAP1 expression, enhancing the efficacy of anti-PD-1 (218). Another study by our group found that DHA increased the abundance of Akkermansia muciniphila by downregulating YAP1, which increased the efficacy of anti-PD-1 (219). These studies confirmed that DHA inhibited HCC progression by inhibiting YAP1. Decursin, a component of Korean Dang-gui (Angelica gigas Nakai) root, significantly inhibited HCC-cell proliferation by upregulating the phosphorylation of LATS1 and β-TrCP and promoting the degradation of YAP1 (220). Myricetin activated LATS1/2 kinase, which directly phosphorylates YAP1 on serine residues, thereby inhibiting HCC cell proliferation (221). Evodiamine significantly inhibited YAP1 expression by upregulating LATS1 phosphorylation, leading to inhibited proliferation and induced apoptosis of HCC cells (222). Wogonin, an ingredient extracted from the Scutellaria baicalensis Georgi root, effectively induced cell cycle arrest and promoted apoptosis in HCC cells by activating MOB1-LATS1 and inhibiting YAP1 and TAZ (223). A study reported that WZ35, a derivative of curcumin, significantly inhibits HCC cell growth by downregulating YAP1-controlled autophagy (92). Ginsenoside CK, an intestinal microbial metabolite of panaxadiol saponins, inhibited HCC proliferation and growth by blocking YAP1/TEAD2 interaction (224). Apigenin decreased YAP1expression by regulating autophagy-related genes, reducing HCC cell migration and invasion (225). Evodiamine, isolated from the Evodia rutaecarpa fruit, is an effective anti-cancer agent that reduces YAP1 levels (226). 4-acetylantrocamol LT3, a new ubiquinone from the mycelium of Antrodia cinna-momea (Polyporaceae), inhibited HepG2 cell growth by targeting the YAP1/TAZ, mTOR and Wnt/β-catenin signaling pathways (227). Tanshinone IIA, an ingredient of Salvia miltiorrhiza, inhibited HCC proliferation by downregulating YAP1 expression in a TGF-β signaling pathway-dependent manner (228). Chinese propolis, a resin-like substance collected by Apis mellifera from various tree buds, inhibited HepG2 cell proliferation and promoted apoptosis by inactivating the Hippo/YAP1 and PI3K/AKT pathways (229). Salvianolic acid B, an active ingredient of Salvia miltiorrhiza, inhibited HCC by upregulating MST1 protein expression, degrading YAP1 in the cytoplasm and inhibiting the expression of downstream genes in the Hippo pathway (230). Ovatodiolide, an active ingredient of Anisomeles indica (L.) Kuntze (Labiatae), significantly reduced YAP1 expression and inhibited the CSC phenotype and associated disease progression (231). Corosolic acid, an extract of Actinidia chinensi, inhibited tumor progression by relocating YAP1 from the nucleus (232). Inhibition of YAP1 by actinomycin D enhanced the efficacy of corosolic acid in HCC treatment (233). Ligustilide, the main ingredient of Angelica sinensis and Ligusticum chuanxiongs (234), antagonized macrophage recruitment and M2 polarization induced by HCC cells by inhibiting YAP1/IL-6-induced IL-6R/STAT3 signaling activation (235). Myricetin, a flavonoid compound found in a wide variety of natural plants (236) and Luteolin, a flavonoid contained in a variety of fruits, vegetables and herbs (237), both showed potential in HCC treatment. Luteolin inhibited the biological effects of matrix stiffness induction and C-X-C motif chemokine receptor type 4-mediated YAP1 signaling pathway in HCC (238). Hydrogen sulfide-releasing oleanolic acid (HS-OA) decreased the expression of YAP1 and its downstream targets CTGF and CYR61, promoting cell apoptosis (239). Daphnane diterpenoids, specifically 12-O-debenzoyl-yuanhuacine, prepared from dried flower buds of the Daphne genkwa plant, effectively inhibited the binding of YAP1 and TEAD1 (240).