TO THE EDITOR
Cholangiocarcinoma (CCA), a highly aggressive malignancy of the biliary tract, continues to present significant clinical challenges, due to its limited therapeutic options and poor prognosis[1,2]. The identification of key molecular drivers and regulatory networks underlying CCA progression has therefore become a research priority, with the hippo-yes-associated protein (YAP) signaling pathway emerging as a critical modulator of tumorigenesis, invasiveness, and therapy resistance[3,4]. Within this context, the role of bile acids, endogenous metabolites intimately associated with biliary tract physiology, has gained increasing attention, as accumulating evidence links their dysregulation to hippo-YAP pathway activation and subsequent CCA development[5,6]. The study by Hu et al[7] published in the World Journal of Gastrointestinal Oncology, offers valuable insights into the bile acid-hippo-YAP axis in CCA. A logical next step to build upon these findings would involve more comprehensive preclinical and, ultimately, clinical studies to assess their therapeutic relevance.
A central insight from Hu et al’s work[7] is the divergent roles of glycochenodeoxycholic acid (GDCA) and deoxycholic acid (DCA) in regulating CCA progression (Figure 1). GDCA has been reported to promote tumor progression by enhancing cell proliferation and inhibiting apoptosis, while DCA has exhibited tumor-suppressive effects under certain conditions, inducing apoptosis and impairing cell migration, their established opposing roles in tumor biology[8]. This duality renders them ideal model compounds for investigating the bile acid-hippo-YAP pathway. Further, the study evaluated the effects of YAP inhibitors and activators on tumor growth, cellular behavior, and molecular signaling pathways, providing insights into potential therapeutic strategies for overcoming this challenging malignancy, with both bile acids exerting their effects through the hippo-YAP pathway. Their experimental data indicate that GDCA promotes CCA progression by inhibiting apoptosis while enhancing proliferation, migration, and invasion. This occurs through suppressing the phosphorylation of mammalian STE20-like protein kinase 1 and large tumor suppressor kinase 1, thereby activating YAP. Conversely, DCA exerts its antitumor effects by enhancing the phosphorylation of mammalian STE20-like protein kinase 1 and large tumor suppressor kinase 1, which inhibits YAP activation. Notably, these effects were reversible upon treatment with YAP modulators, both in vitro and in vivo, underscoring the functional centrality of the hippo-YAP axis in mediating bile acid-driven oncogenesis. This observation is particularly notable, given the established association between bile acid dysmetabolism and biliary tract disorders, including CCA[9,10], it provides a mechanistic link that bridges metabolic alterations to oncogenic signaling. By demonstrating that YAP targeted interventions can counteract the pro-tumorigenic outcomes induced by these bile acids, the study also underscores the therapeutic potential of targeting this pathway in bile acid-driven CCA. Such findings align with broader research emphasizing YAP as a promising therapeutic target in solid tumors, offering a rationale for the development of YAP inhibitors tailored to CCA subsets defined by bile acid profiles.
Figure 1 Glycodeoxycholic acid and deoxycholic acid exert opposing effects on yes-associated protein activation via the mammalian STE20-like protein kinase 1/large tumor suppressor kinase 1 axis.
Glycodeoxycholic acid inhibits the phosphorylation of mammalian STE20-like protein kinase 1 and large tumor suppressor kinase 1, thereby promoting yes-associated protein phosphorylation and nuclear translocation, which subsequently activates the expression of genes associated with tumor migration and invasion. In contrast, deoxycholic acid exerts the opposite regulatory effect. GDCA: Glycodeoxycholic acid; DCA: Deoxycholic acid; MST1: Mammalian STE20-like protein kinase 1; LATS1: Large tumor suppressor kinase 1; YAP: Yes-associated protein; TEAD: Transcriptional enhanced associate domain.
Despite these contributions, the study’s limitations must be acknowledged to contextualize its findings and guide future research. The reliance on a single CCA cell line (HuCCT1) represents a major constraint, as cell line-specific genetic and phenotypic characteristics may not reflect the heterogeneity of human CCA. CCA is a morphologically and molecularly diverse disease, with subtypes differing in their etiology, genetic drivers, and response to therapy; thus, findings derived from a single model are unlikely to be generalizable across the entire disease spectrum. A further limitation is that the focus on only two bile acids overlooks the complexity of the bile acid pool, which comprises a diverse array of primary and secondary bile acids with distinct chemical properties and biological activities[11,12] (Figure 2). For instance, studies have shown that other bile acids, such as the primary bile acids glycocholic acid (typically upregulated in CCA patients) and taurocholic acid (often downregulated), also exhibit disease-specific alterations and may modulate receptors like Takeda G protein-coupled receptor 5 (TGR5) and sphingosine 1-phosphate receptor 2, which are implicated in CCA progression[13]. Exploring the effects of other clinically relevant bile acids, such as chenodeoxycholic acid and lithocholic acid, could provide a more comprehensive understanding of how bile acid composition influences CCA progression.
Figure 2 Primary bile acids are synthesized in the liver from cholesterol via the classical or alternative pathway.
Upon entering the intestine, they are metabolized by gut microbiota into secondary bile acids. Approximately 90%-95% of these are reabsorbed in the terminal ileum and recycled by the liver through enterohepatic circulation. BA: Bile acid; CA: Cholic acid; GCA: Glycocholic acid; TCA: Taurocholic acid; CDCA: Chenodeoxycholic acid; GDCA: Glycodeoxycholic acid; TDCA: Taurodeoxycholic acid; DCA: Deoxycholic acid; UDCA: Ursodeoxycholic acid; GUDCA: Glycoursodeoxycholic acid; TUDCA: Tauroursodeoxycholic acid; LCA: Lithocholic acid; GLCA: Glycolithocholic acid; TLCA: Taurolithocholic acid.
Equally important is the study’s limited exploration of pathway crosstalk, which constrains the depth of mechanistic insight. The hippo-YAP pathway does not operate in isolation; it interacts extensively with other oncogenic signaling cascades, including the Wnt/β-catenin, mitogen-activated protein kinase, and phosphoinositide 3-kinase/protein kinase B pathways[14-16], all of which are frequently dysregulated in CCA. For example, YAP has been shown to physically interact with β-catenin in intrahepatic CCA, and their cooperative transcriptional activity is required for full oncogenic transformation[16] (Figure 3). Bile acids themselves are known to activate multiple receptors, such as the farnesoid X receptor (FXR) and TGR5, which may mediate crosstalk with the hippo-YAP pathway. In fact, studies have demonstrated that YAP recruits the nucleosome remodeling and deacetylase repressive complex to inhibit the transcriptional activity of the FXR, leading to impaired bile acid efflux. Conversely, the TGR5 signaling pathway can regulate YAP through a cyclic adenosine monophosphate-protein kinase A-dependent mechanism (Figure 4). Elucidating these interactive networks is crucial for comprehending the full scope of bile acid-mediated CCA regulation, while also helping to avoid potential off-target effects that may arise from YAP-targeted therapies. For instance, if a bile acid simultaneously activates YAP and inhibits FXR, targeting YAP alone may not fully abrogate the pro-tumorigenic signal, highlighting the need for combinatorial targeting strategies.
Figure 3 Yes-associated protein/β-catenin-transcriptional enhanced associate domain complex drives oncogenic transcription.
Yes-associated protein interacts with β-catenin to form a potent transcriptionally active yes-associated protein-transcriptional enhanced associate domain-β-catenin ternary complex, which drives the expression of pro-oncogenic genes. YAP: Yes-associated protein; TEAD: Transcriptional enhanced associate domain.
Figure 4 Yes-associated protein-mediated transcription inhibition and feedback activation of farnesoid X receptor by taurocholate.
Yes-associated protein (YAP) activated by taurocholic acid recruits histone deacetylase 1 through the YAP-transcriptional enhanced associate domain complex, thereby suppressing the transcriptional activity of farnesoid X receptor. Concurrently, accumulated taurocholic acid further activates YAP through a feedback mechanism involving receptors such as sphingosine 1-phosphate receptor 2. YAP: Yes-associated protein; TEAD: Transcriptional enhanced associate domain; HDAC: Histone deacetylase; FXR: Farnesoid X receptor; TCA: Taurocholic acid; BA: Bile acid.
To address these gaps, future research should prioritize validation of Hu et al’s findings[7] using diverse experimental models, including multiple CCA cell lines, patient-derived organoids, and in vivo xenograft or genetically engineered mouse models. Patient-derived organoids, in particular, offer a valuable tool for recapitulating the molecular and phenotypic heterogeneity of human CCA, enabling more clinically relevant assessments of bile acid-hippo-YAP interactions. In parallel, investigations into multi-pathway crosstalk should integrate genomic, transcriptomic, and proteomic approaches to map comprehensive signaling networks. Such studies could also explore the clinical relevance of bile acid profiles and YAP activation status in CCA patients, potentially identifying prognostic biomarkers or predictive factors for YAP targeted therapies. Moreover, given the emerging role of the tumor microenvironment in CCA, studies indicate that excessive taurocholic acid and glycocholic acid specifically activate the bile acid receptor G protein-coupled bile acid receptor 1 on cancer-associated fibroblasts, leading to the upregulation of the chemokine C-X-C motif ligand 10 enhancing epithelial-mesenchymal transition and metastasis in CCA cells. This process fosters an immunosuppressive tumor microenvironment by recruiting neutrophils[17]. Furthermore, CDCA modulates the secretion of C-X-C motif ligand 16 by hepatic sinusoidal endothelial cells, thereby recruiting and activating natural killer T cells with antitumor activity[18]. Future work should examine how matrix components promote YAP activation and therapeutic resistance.
Conclusion
In conclusion, the study by Hu et al[7] provides important preliminary evidence for the role of specific bile acids in regulating CCA progression via the hippo-YAP pathway, offering a foundation for further mechanistic and translational exploration. By combining diverse experimental models, systems-level analyses of pathway crosstalk, and clinical correlation studies, researchers can advance our understanding of this disease and pave the way for the development of more effective, personalized therapeutic strategies for CCA patients.
