Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is a complex metabolic disorder characterized by hepatic lipid accumulation, inflammation, and fibrosis (He et al., 2025). This pathogenesis is driven by dysregulation of glucose, lipid, and cholesterol metabolism (Marroncini et al., 2024). Due to its protective role in metabolic and inflammatory processes, TGR5 has been widely researched in MASLD (Wei et al., 2024). A central piece of evidence for its protective function is the observed decrease in hepatic TGR5 expression in both MASLD patients and experimental models, coupled with the exacerbation of pathology in TGR5^−/− mice (Shi et al., 2021). This protective role is further demonstrated by studies showing that TGR5 activation by BAs, synthetic agonists, or natural compounds can alleviate hepatic steatosis, inflammation, and disease progression (He et al., 2024; Yang et al., 2019; Li et al., 2024a; Gillard et al., 2022b; Gillard et al., 2022a).

TGR5 has been proven to regulate blood glucose levels in multiple ways. A well-established pathway involves TGR5-mediated induction of intestinal glucagon-like peptide-1 (GLP-1) release, which improves pancreatic and hepatic function and enhances glucose tolerance, as confirmed by pharmacological and genetic studies (Thomas et al., 2009). Consequently, TGR5-deficient male mice on a high-fat diet exhibit exacerbated insulin resistance compared to their wild-type littermates (Vassileva et al., 2010). This preclinical evidence is supported by clinical research, in which curcumin was found to improve MASLD parameters by modulating gut microbiota-dependent BA metabolism and activating TGR5, thereby reducing fasting blood glucose, triglycerides, and insulin levels (He et al., 2024). Beyond peripheral actions, TGR5 activation also contributes to the regulation of glucose homeostasis within the hypothalamus (Zizzari et al., 2025). Additionally, TGR5 activation has been shown to lower plasma free fatty acids, hepatic triglycerides, and cholesterol levels in various MASLD-related models (Thomas et al., 2009; Finn et al., 2019). In energy metabolism, TGR5 signaling in brown adipose tissue—via the TGR5-cAMP-type 2 iodothyronine deiodinase (D2) pathway—promotes energy expenditure and protects against obesity (Watanabe et al., 2006). TGR5 also upregulates mitochondrial uncoupling protein expression and stimulates hormone-sensitive lipase phosphorylation in adipose tissue, conferring metabolic improvements in diet-induced obese mice (Ding et al., 2021).

Beyond its metabolic actions, TGR5 also counteracts MASLD through its anti-inflammatory properties, targeting the chronic inflammatory signaling that promotes hepatic insulin resistance in obesity (Cai et al., 2005). In regulating inflammation and metabolism, TGR5 and FXR often exhibit synergistic effects in the liver (Häussinger and Keitel, 2018). FXR activation improves metabolic homeostasis primarily through two mechanisms. On one hand, it lowers blood glucose by inhibiting gluconeogenesis and promoting glycogen storage, processes mediated by fibroblast growth factor 19/15. On the other hand, it reduces liver fat by suppressing lipogenesis, which occurs through the small heterodimer partner-mediated inhibition of transcription factors like sterol regulatory element-binding protein 1c (Abdel-Rasol and El-Sayed, 2025). Furthermore, FXR was also reported to directly bind the promoter region of NFKB1 to inactivate NF-κB signaling and suppress inflammation (Jing et al., 2026). Consequently, research interest is growing in dual FXR/TGR5 agonists as a therapeutic strategy for MASLD, with several candidates demonstrating promising efficacy (Zhang et al., 2025; Comeglio et al., 2018; Marchianò et al., 2023). Indeed, simultaneous activation of both receptors is increasingly viewed as a more potent approach than single-receptor targeting for managing metabolic diseases (Pathak et al., 2017; Jadhav et al., 2018; Roth et al., 2018). However, this field contains conflicting findings. For instance, Wang X et al. reported that the dual agonist INT-767 ameliorated western diet–induced MASLD progression exclusively through FXR-dependent mechanisms, with its effects persisting in TGR5 knockout mice but being abolished in FXR knockout mice (Wang et al., 2022). This apparent discrepancy may arise from the unbalanced potency of INT-767, which is a potent FXR agonist (EC₅₀ = 30 nM) but a much weaker TGR5 agonist (EC₅₀ = 630 nM), resulting in a 21-fold selectivity bias (Rizzo et al., 2010). This underscores the importance of evaluating next-generation, balanced dual agonists (e.g., BAR502) as potential therapies for MASLD. Furthermore, the cell-specific effects of TGR5 activation add another layer of complexity. A recent study revealed that while TGR5 activation in macrophages protects against MASLD progression, its activation in hepatocytes may conversely promote the transition to MASH (Lian et al., 2025). Therefore, future drug development must consider not only receptor agonistic efficacy but also tissue- and cell-type-specific targeting of TGR5.

Cholestatic liver diseases, characterized by impaired bile flow and the accumulation of cytotoxic BAs in the liver, lead to progressive hepatobiliary injury, inflammation, and fibrosis. TGR5, a receptor pivotal in these processes, is abundantly expressed in bile duct cells, as evidenced by its co-localization with the cholangiocyte marker CK-19 (CK19, cholangiocyte marker) (Keitel et al., 2008), and is also present in gallbladder epithelial and smooth muscle cells (Li et al., 2011; Lavoie et al., 2010). Its activation in cholangiocytes exerts multiple protective effects: it stimulates chloride secretion and subsequent bicarbonate-rich choleresis, which mitigates the toxicity of BAs (Guo et al., 2024; Yu et al., 2023), and it regulates the biliary epithelial barrier by modulating JAM-A expression and phosphorylation, thereby preventing bile leakage (Merlen et al., 2020). Furthermore, TGR5 exhibits a complex, cell type-specific role in cholangiocyte proliferation, promoting it in nonciliated cells while inhibiting it in ciliated cells (Masyuk et al., 2013). Given its integral role in governing cholangiocyte secretion, barrier function, and proliferation, TGR5 is a significant player in cholestasis-related diseases.

Beyond its direct effects on cholangiocytes, TGR5 modulates cholestatic liver injury by exerting potent anti-inflammatory effects, primarily through the inhibition of the NF-κB and NLRP3 signaling pathways (Yao et al., 2023; Zhuang et al., 2024). The cell-specific role of TGR5 is complex. Single-cell sequencing revealed that its expression is predominantly high in immune cells, such as macrophages and NKT cells, but relatively low in cholangiocytes. This explains why the overall hepatic TGR5 level can be elevated in primary sclerosing cholangitis (PSC) patients due to immune cell infiltration, despite a disease-associated downregulation of TGR5 specifically within the inflamed biliary epithelium (Di Giorgio et al., 2025; Reich et al., 2021). The functional importance of TGR5 is underscored by in vivo evidence: TGR5^−/− mice develop more severe liver injury, inflammation, and fibrosis (Rao et al., 2020), whereas activation of TGR5 by specific agonists (e.g., BAR501) or natural compounds (e.g., total astragalus saponins) effectively attenuates cholestatic injury in mouse models of PSC (Di Giorgio et al., 2025; Zhou et al., 2024). Although TGR5 shows promising therapeutic effects for cholestatic diseases, its broad expression characteristics have led to many significant side effects that cannot be ignored. Systemic TGR5 activation has been also reported to worsen pruritus in cholestasis (Alemi et al., 2013; Abu-Hayyeh et al., 2016). The activation of TGR5 in gallbladder smooth muscle cells causes smooth muscle relaxation and promotes gallbladder filling (Lavoie et al., 2010; Li et al., 2011), thereby increasing the risk of cholecystitis and cholelithiasis. These unwanted side effects have become an obstacle to the application of TGR5 agonists (Han et al., 2020).

Liver fibrosis, a shared pathological outcome of chronic liver diseases, is characterized by excessive extracellular matrix (ECM) deposition, with HSC activation serving as its central driver. The role of the bile acid receptor TGR5 in this process is complex and exhibits distinct cell-type specificity. Several studies report on a protective role for TGR5. For instance, TGR5 has been shown to suppress HSC activation by inducing apoptosis and inhibiting both Smad-dependent and Smad-independent TGF-β signaling pathways (Shao et al., 2022). Similarly, global TGR5 knockout was found to exacerbate liver fibrosis, and its activation was shown to inhibit HSC activation by attenuating mitochondrial fission, further supporting an overall protective function (Sun et al., 2024). In contrast, other evidence points to a cell-autonomous, pro-fibrotic role within HSCs. Specifically, HSC-specific knockdown of TGR5 was shown to attenuate fibrotic progression (Xie et al., 2021). Mechanistically, in HSCs, TGR5 activation promote the proliferation and activation of HSCs via ERK1/2 and p38 MAPK pathways (Xie et al., 2021). This apparent discrepancy may stem from fundamental differences in experimental models. The studies suggesting a protective role employed global TGR5 knockout, which reflects the net effect of TGR5 loss across all cell types. Conversely, HSC-specific knockdown isolates the function of TGR5 within HSCs themselves, revealing a direct pro-fibrotic signaling role. Thus, TGR5 appears to exert an overall protective role in liver fibrosis at the organismal level, while simultaneously driving a cell-autonomous, pro-fibrotic program within activated HSCs. This dual role highlights the context-dependent nature of TGR5 signaling, though further studies are needed to fully elucidate the conditions that dictate its functional outcome.

The involvement of TGR5 in liver fibrosis extends beyond HSCs to encompass a multicellular regulatory network, wherein it primarily exerts anti-inflammatory and vasomodulatory effects. On one hand, in macrophages, TGR5 activation promotes a metabolic switch from glycolysis to oxidative phosphorylation via the ATP-citrate lyase/Akt pathway, thereby favoring the anti-inflammatory M2 phenotype (Shao et al., 2022). On the other hand, in, LSECs, TGR5 activation counteracts endothelial dysfunction in cirrhotic portal hypertension. It upregulates the expression and activity of cystathionine-γ-lyase (CSE) and endothelial nitric oxide synthase (eNOS) in LSECs, while suppressing endothelin-1 (ET-1) expression via an Akt-dependent FOXO1 phosphorylation mechanism wherein Akt phosphorylates and inactivates the transcription factor FOXO1, which otherwise promotes ET-1 transcription (Renga et al., 2015b; Fiorucci and Distrutti, 2016; Renga et al., 2015a). This restores the balance between vasodilatory and vasoconstrictive forces.

In summary, although TGR5 may exert a direct pro-fibrotic effect within HSCs, its potent anti-inflammatory actions on immune cells (Marchianò et al., 2025; Shao et al., 2022; Di Giorgio et al., 2025) and its vasoprotective benefits on LSECs collectively result in a net anti-fibrotic outcome. The systemic effect likely involves intercellular communication, such as anti-inflammatory cytokines from macrophages (e.g., IL-10) further suppressing HSC activation, and improved LSEC function helping to deactivate HSCs through a healthy paracrine environment, Therefore, systemic TGR5 activation represents a promising therapeutic strategy for liver fibrosis and associated complications, though its cell-specific effects warrant careful evaluation.

HCC, a highly invasive cancer arising from chronic liver disease and cirrhosis, represents a leading cause of cancer-related mortality worldwide (Wu et al., 2021). The BA receptor TGR5, which regulates energy homeostasis, glucose metabolism, and immunomodulation via cAMP, AKT, and NF-κB signaling pathways, is implicated in hepatic oncogenesis (Li et al., 2019; Qi et al., 2022). Accumulating clinical and mechanistic evidence suggests a tumor-promoting role for TGR5 in HCC. The methylation level of the circulating TGR5 promoter is significantly elevated in patients with HBV-related HCC, indicating its close association with the disease. Furthermore, TGR5 expression is significantly higher in HCC tissues compared to cirrhotic or normal liver tissues, and this upregulation is correlated with bone metastasis and poor patient prognosis (Chen et al., 2023) Mechanistically, the oncogene α7-nicotinic acetylcholine receptor (α7-nAChR) promotes HCC recurrence by upregulating TGR5 and activating the TGR5/JAK2/STAT3 signaling axis, subsequently enhancing the expression of RhoA, ROCK1, MMP2, and MMP9 proteins that facilitate cancer invasion and metastasis (Li et al., 2019). Despite these findings, the role of TGR5 in liver cancer remains complex. While TGR5 has been reported to exert anti-cancer effects in other malignancies (Guo et al., 2015; Su et al., 2017), such a tumor-suppressive function is scarcely documented in HCC, with one supporting study having been retracted. In contrast to the HCC-promoting evidence, numerous studies have unequivocally established the protective roles of TGR5 in HCC precancerous lesions (such as inflammation, metabolic dysfunction, cholestasis, and fibrosis). This raises a pivotal scientific question: following the malignant transformation of hepatocytes, does the function of TGR5 undergo a “switch” from protective to promotive, or is its protective signaling “hijacked” or masked by oncogenic pathways? Currently, precise and systematic investigations into TGR5 across different stages of hepatocarcinogenesis, particularly during the evolution from precancerous lesions to invasive cancer, remain limited. Future research should employ stage-specific genetically engineered animal models, cell-type-specific gene knockout techniques, and longitudinal clinical cohort analyses to elucidate the detailed role of TGR5 in the dynamic progression of HCC and to evaluate its potential as a stage-specific therapeutic target.