Bile acid receptor signaling in metabolic dysfunction-associated steatotic liver disease: Mechanistic insights and emerging therapeutic strategies

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, spanning a spectrum from simple steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In addition to liver-related morbidity, MASLD is closely associated with systemic metabolic dysfunction and increased cardiovascular risk, emphasizing the need for mechanism-based therapies. Bile acids are now recognized as key metabolic and immunological signaling molecules acting through receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor Takeda G-protein-coupled receptor 5. This narrative review summarizes current evidence on bile acid receptor signaling in MASLD, focusing on receptor biology, molecular mechanisms, and emerging therapeutic strategies. We discuss how changes in bile acid composition, receptor responsiveness, and downstream signaling contribute to metabolic dysregulation, inflammation, and fibrogenesis, while acknowledging inter-individual heterogeneity and limited stage-specific human data. Particular attention is given to FXR and Takeda G-protein-coupled receptor 5 signaling, their interaction with metabolic and inflammatory pathways, and modulation by gut microbiota-derived bile acid transformations. We also review clinical and translational data on bile acid-targeted therapies, including FXR agonists and norursodeoxycholic acid, highlighting therapeutic promise alongside challenges related to lipid effects, long-term safety, and variable efficacy. Overall, bile acid signaling represents a promising yet complex therapeutic axis in MASLD.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Bile acid receptors; Farnesoid X receptor; Takeda G-protein-coupled receptor 5; Norursodeoxycholic acid

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health challenge with limited pharmacological options. This review highlights the emerging role of bile acid receptors - particularly farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 - as therapeutic targets in MASLD. It synthesizes recent advances in receptor signaling, gut microbiota-bile acid interactions, and the development of FXR agonists, norursodeoxycholic acid, and dual FXR/Takeda G-protein-coupled receptor 5 agents. The review also outlines future directions in precision hepatology, proposing receptor-specific, microbiome-informed strategies for managing MASLD.

INTRODUCTION

The global burden of metabolic liver disease has undergone a conceptual transformation with the introduction of metabolic dysfunction-associated steatotic liver disease (MASLD), a new diagnostic category that replaces non-alcoholic fatty liver disease. MASLD is now defined by hepatic steatosis in the presence of at least one of five cardio-metabolic risk factors: Obesity, type 2 diabetes (T2D), hypertension, dyslipidemia, or insulin resistance[1]. This redefinition aligns the disease more closely with its systemic metabolic underpinnings and highlights its interconnection with cardiovascular, renal, and endocrine dysfunctions.

MASLD has emerged as the most prevalent chronic liver disease globally, with a particularly high burden among individuals with T2D, where its prevalence exceeds 70%[2-4]. It encompasses a continuum from simple hepatic steatosis to the more progressive metabolic dysfunction-associated steatohepatitis (MASH), advancing to significant fibrosis, cirrhosis, and hepatocellular carcinoma. Notably, approximately one in five individuals with T2D are at high risk of developing cirrhosis, placing MASLD among the leading indications for liver transplantation in the United States[2-4]. Beyond liver-specific outcomes, MASLD is independently associated with increased risk for T2D progression, cardiovascular disease, extrahepatic malignancies, and all-cause mortality[1]. Despite its substantial health and economic burden, MASLD remains underdiagnosed and undertreated in clinical practice, underscoring the critical need for early identification, non-invasive risk stratification, and timely intervention to prevent irreversible liver damage and associated complications. Importantly, although MASLD represents a progressive disease spectrum, the molecular mechanisms driving its evolution across different stages are not fully delineated, and available evidence suggests considerable biological heterogeneity between early and advanced disease.

Despite decades of investigations on pharmacologic agents, lifestyle interventions remain the mainstay of management. However, long-term adherence to lifestyle change is challenging, and many patients, particularly those with advanced fibrosis or high metabolic burden, require pharmacologic intervention. Conventional therapies targeting insulin resistance, lipotoxicity, and inflammation - such as thiazolidinediones, vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 inhibitors - have shown variable efficacy and limited histological improvement[5]. Thus, there is an urgent need to explore novel mechanistic pathways for therapeutic intervention.

One of the most promising therapeutic avenues is the modulation of bile acid signaling pathways. Once thought to be simple digestive detergents, bile acids are now recognized as potent metabolic and immunological signaling molecules. They exert systemic effects via nuclear receptors such as the farnesoid X receptor (FXR) and membrane-bound G protein-coupled receptors, particularly Takeda G-protein-coupled receptor 5 (TGR5)[6]. Activation of these receptors regulates hepatic lipid and glucose metabolism, insulin sensitivity, bile acid homeostasis, and inflammation - all key processes in MASLD pathogenesis. Nevertheless, receptor expression levels, bile acid pool composition, and downstream signaling activity appear to vary across disease stages, and stage-resolved human data remains limited and heterogeneous.

Agents targeting these receptors, including FXR agonists [e.g., obeticholic acid (OCA), cilofexor] and norursodeoxycholic acid (norUDCA), have demonstrated promising effects in preclinical models and early-phase clinical trials[6]. FXR activation reduces de novo lipogenesis, enhances insulin signaling, and suppresses inflammation and fibrosis, while norUDCA exerts anti-inflammatory and anti-fibrotic effects via bicarbonate-rich choleresis and cholehepatic shunting[6]. Moreover, TGR5 activation enhances energy expenditure and glucose metabolism via gut hormones such as GLP-1, suggesting potential synergy with incretin-based therapies[7].

Recent insights into gut microbiota-bile acid interactions have further expanded the therapeutic horizon. Alterations in gut microbial composition affect bile acid composition, receptor activation, and enterohepatic circulation, making the gut-liver axis a viable target for combination therapy in MASLD.

This review aims to provide a comprehensive narrative synthesis of bile acid signaling pathways as emerging therapeutic targets in MASLD, emphasizing molecular mechanisms, receptor biology, and current pharmacologic strategies. Special focus is placed on FXR and TGR5 pathways, along with current and investigational agents such as OCA, norUDCA, and dual FXR/TGR5 agonists. Given the heterogeneity of available evidence, this review primarily discusses overarching mechanistic trends rather than offering a detailed, stage-specific quantitative comparison of receptor expression or bile acid profiles. In doing so, we seek to bridge basic science with translational hepatology and offer insights into future therapeutic development for MASLD.

LITERATURE REVIEW

This narrative review was conducted to comprehensively synthesize current knowledge on bile acid receptors and their signaling pathways as therapeutic targets in MASLD. A structured literature search was performed across PubMed, Scopus, Web of Science, and Google Scholar for English-language publications between January 2000 and November 2025 using combinations of terms including “MASLD”, “NAFLD”, “FXR”, “TGR5”, “norUDCA”, “obeticholic acid”, “bile acid signaling”, “FGF19”, and “gut-liver axis”. Eligible sources included preclinical studies, mechanistic research, translational models, and clinical trials focused on bile acid receptor function and modulation in metabolic liver disease. Reference lists of relevant articles and reviews were hand-screened to identify additional studies. Articles were included if they explored molecular mechanisms, receptor biology [FXR, TGR5, small heterodimer partner (SHP), fibroblast growth factor 19 (FGF19)], pharmacologic interventions (e.g., OCA, norUDCA), or gut microbiome interactions relevant to MASLD. Studies exclusively addressing cholestatic liver diseases without metabolic relevance, non-peer-reviewed content, and editorials were excluded. Extracted findings were thematically synthesized around key molecular pathways, therapeutic mechanisms, and translational relevance.

Given the heterogeneity of the included literature - spanning basic mechanistic experiments, animal models, translational studies, and small to medium-sized clinical trials - a formal quality assessment or quantitative scoring system was not performed. Instead, emphasis was placed on mechanistic plausibility, internal consistency, reproducibility across studies, and translational relevance to MASLD pathophysiology.

It is acknowledged that substantial heterogeneity exists among the included studies with respect to study design, sample size, experimental models (animal vs human), and outcome measures (histology, biochemical markers, imaging-based endpoints, or metabolic parameters). These differences may influence the strength, comparability, and generalizability of individual findings, particularly when extrapolating preclinical observations to clinical disease. This limitation was considered when interpreting and synthesizing the overall conclusions of the review.

BILE ACID BIOLOGY AND RECEPTOR SIGNALING IN HEALTH AND MASLD

Bile acids, once regarded primarily as amphipathic molecules critical for lipid digestion and absorption, are now recognized as multifaceted endocrine regulators that play a central role in systemic metabolic homeostasis. Synthesized in hepatocytes from cholesterol via the classical [cholesterol 7α-hydroxylase (CYP7A1)-mediated] and alternative (sterol 27-hydroxylase-mediated) pathways, primary bile acids [cholic acid (CA) and chenodeoxycholic acid (CDCA)] are conjugated and secreted into bile via bile salt export pump, stored in the gallbladder, and released into the intestinal lumen postprandially[8]. In the terminal ileum, they are actively reabsorbed by the apical sodium-dependent bile acid transporter and returned to the liver via the portal circulation through the coordinated action of organic solute transporters (α/β) on enterocyte and sodium taurocholate cotransporting polypeptide on hepatocyte, completing the enterohepatic cycle (Figure 1)[9].

Figure 1 Enterohepatic circulation of bile acids and bacterial deconjugation. Bile acids are synthesized in the liver from cholesterol via two major pathways: The classic pathway mediated by cholesterol 7α-hydroxylase and the alternative pathway mediated by sterol 27-hydroxylase. Newly synthesized bile acids are secreted into the bile canaliculi through bile salt export pump and stored in the gallbladder, from where they are released into the intestine in response to meals. In the terminal ileum, bile acids are actively reabsorbed across the apical membrane by apical sodium-dependent bile acid transporter and exported across the basolateral membrane into the portal circulation via the heteromeric transporters organic solute transporter alpha/beta. Reabsorbed bile acids return to the liver through the portal vein, where they are taken up into hepatocytes by sodium taurocholate cotransporting polypeptide, completing the enterohepatic circulation. Within the ileum, bile acids activate the nuclear receptor farnesoid X receptor, inducing secretion of fibroblast growth factor 19, which feeds back to the liver to suppress bile acid synthesis. In the colon, gut microbiota expressing enzymes such as bile salt hydrolase and 7α-dehydroxylase convert primary bile acids into secondary bile acids, shaping the circulating bile acid pool. Bile acids also activate Takeda G-protein-coupled receptor 5 on enteroendocrine cells, promoting glucagon-like peptide-1 release and linking bile acid signaling to metabolic regulation. NTCP: Sodium taurocholate cotransporting polypeptide; PBA: Primary bile acid; CYP7A1: Cholesterol 7α-hydroxylase; CYP27A1: Sterol 27-hydroxylase; CA: Cholic acid; CDCA: Chenodeoxycholic acid; BSEP: Bile salt export pump; ASBT: Apical sodium-dependent bile acid transporter; FXR: Farnesoid X receptor; FGF19: Fibroblast growth factor 19; OST: Organic solute transporter; TGR5: Takeda G-protein-coupled receptor 5; GLP-1: Glucagon-like peptide-1; TCA: Taurocholic acid; GCA: Glycocholic acid; TCDCA: Taurochenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; CA: Cholic acid; DCA: Deoxycholic acid; LCA: Lithocholic acid.

Beyond their digestive role, bile acids serve as signaling molecules that interact with nuclear and membrane-bound receptors to modulate lipid and glucose metabolism, immune responses, energy homeostasis, and fibrogenesis. Among these, the FXR is a nuclear receptor highly expressed in hepatocytes and ileal enterocytes. Upon activation, primarily by CDCA, FXR represses CYP7A1 expression via the SHP, thereby limiting de novo bile acid synthesis. FXR also induces FGF19 in the intestine, which signals through hepatic fibroblast growth factor receptor 4/β-klotho to inhibit gluconeogenesis and lipogenesis, and enhance glycogen storage (Figure 2)[10]. In early stages of MASLD, FXR signaling appears to be relatively preserved but functionally dysregulated, suggesting partial compensatory activation in response to metabolic stress.

Figure 2 Bile acid-induced activation of farnesoid X receptor and Takeda G-protein-coupled receptor 5 with downstream signaling relevant to metabolic dysfunction-associated steatotic liver disease. This figure illustrates two complementary bile acid-activated signaling pathways - farnesoid X receptor (FXR), a nuclear receptor, and Takeda G-protein-coupled receptor 5 (TGR5), a membrane-bound G-protein-coupled receptor - and their roles in metabolic dysfunction-associated steatotic liver disease. FXR is activated by bile acids, particularly chenodeoxycholic acid, and by pharmacologic agonists including obeticholic acid, tropifexor, and cilofexor. In hepatocytes, FXR activation induces small heterodimer partner, which suppresses cholesterol 7α-hydroxylase, thereby reducing bile acid synthesis. FXR signaling increases low-density lipoprotein receptor expression and suppresses sterol regulatory element-binding protein-1c, leading to reduced hepatic lipogenesis. Concurrently, FXR inhibits nuclear factor kappa B, attenuating inflammatory signaling, and downregulates profibrotic mediators such as transforming growth factor-β1 and collagen type I alpha-1 chain, thereby limiting hepatic fibrosis. In the ileum, FXR activation stimulates secretion of fibroblast growth factor 19, which acts on hepatic fibroblast growth factor receptor 4 to suppress gluconeogenesis and improve insulin sensitivity. In parallel, TGR5 is activated predominantly by secondary bile acids and by dual or selective agonists such as INT-767 and BAR502. In intestinal L cells, TGR5 activation enhances secretion of glucagon-like peptide-1, promoting insulin sensitivity and glycemic control. In hepatic Kupffer cells and macrophages, TGR5 signaling suppresses pro-inflammatory cytokine production through inhibition of nuclear factor kappa B. In brown adipose tissue, TGR5 activation increases intracellular cyclic adenosine monophosphate, triggering protein kinase A-mediated induction of type 2 iodothyronine deiodinase, thereby enhancing mitochondrial activity and energy expenditure. Collectively, FXR and TGR5 signaling converge to reduce lipogenesis, inflammation, and fibrosis while improving insulin sensitivity and energy balance, highlighting these bile acid-responsive pathways as key therapeutic targets in metabolic dysfunction-associated steatotic liver disease. A: Farnesoid X receptor signaling; B: Takeda G-protein-coupled receptor 5 signaling. FXR: Farnesoid X receptor; CDCA: Chenodeoxycholic acid; OCA: Obeticholic acid; SHP: Small heterodimer partner; LDLR: Low-density lipoprotein receptor; SREBP-1c: Sterol regulatory element-binding protein 1c; NF-κB: Nuclear factor kappa B; TGF: Transforming growth factor; COL1α1: Collagen type I alpha 1 chain; CYP7A1: Cholesterol 7α-hydroxylase; FGFR4: Fibroblast growth factor receptor 4; TGR5: Takeda G-protein-coupled receptor 5; GPCR: G protein-coupled receptor; BA: Bile acid; GLP-1: Glucagon-like peptide-1; cAMP: Cyclic adenosine monophosphate; PKA: Protein kinase A; DIO2: Type 2 iodothyronine deiodinase.

FXR’s relevance in MASLD is multifactorial. Activation of FXR improves insulin sensitivity by downregulating gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase), lowers triglyceride accumulation by inhibiting sterol regulatory element-binding protein 1c, and exerts anti-inflammatory and anti-fibrotic effects via inhibition of nuclear factor kappa B (NF-κB) signaling and suppression of hepatic stellate cell activation[11]. These properties make FXR a compelling therapeutic target for steatosis, steatohepatitis, and fibrosis - key features in the progression from simple MASLD to MASH. However, available evidence suggests that FXR responsiveness progressively declines with advancing fibrosis and cirrhosis, potentially limiting the effectiveness of FXR-mediated signaling in advanced disease stages.

Complementing FXR is TGR5, a G protein-coupled receptor, predominantly activated by secondary bile acids [e.g., lithocholic acid (LCA)]. Expressed in Kupffer cells, cholangiocytes, brown adipose tissue, and enteroendocrine L cells, TGR5 signaling leads to increased intracellular cyclic adenosine monophosphate (cAMP), which activates the protein kinase A-cAMP response element-binding protein pathway[12]. In intestinal epithelial cells, this cascade promotes GLP-1 secretion, enhancing insulin sensitivity and glucose control. In immune cells, TGR5 reduces cytokine production, mitigating hepatic inflammation. In adipose tissue and muscle, TGR5 stimulation increases energy expenditure through extracellular regulated kinase 1/2 and mitochondrial activation, adding another dimension to its therapeutic promise (Figure 2)[11,12]. The relative contribution of TGR5 signaling may therefore increase as bile acid composition shifts toward secondary species during disease progression.

In the context of MASLD, both bile acid composition and signaling are disrupted. Patients exhibit elevated total bile acid levels, reduced FXR activity, altered FGF19 signaling, and increased pro-inflammatory and fibrogenic stimuli. As MASLD progresses, the bile acid pool tends to become more hydrophobic, with a relative enrichment of secondary bile acids, which may further exacerbate receptor imbalance and inflammatory signaling. CDCA and LCA have been shown to activate pro-inflammatory pathways such as toll-like receptor 4 and mitogen-activated protein kinase, contributing to the progression from steatosis to NASH and fibrosis. Conversely, FXR and vitamin D receptor (VDR) can attenuate fibrosis by inhibiting transforming growth factor (TGF)-β1 and collagen type I alpha-1 chain expression, respectively[10,13]. Similarly, nuclear receptors like constitutive androstane receptor (CAR) activate the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, providing antioxidant and anti-inflammatory benefits[14]. In contrast, activation of pregnane X receptor (PXR) impairs insulin signaling and promotes insulin resistance, thereby worsening MASLD[15].

Furthermore, recent data underscores the role of the gut microbiota in shaping bile acid signaling. Intestinal microbes convert primary bile acids into secondary bile acids, thereby modulating the balance of FXR vs TGR5 activation. Dysbiosis - commonly seen in MASLD - can impair this balance, shifting the bile acid profile toward pro-inflammatory and insulin-desensitizing metabolites, thereby aggravating liver injury and systemic metabolic dysfunction[16].

A comprehensive summary of bile acid receptor functions, their ligands, and downstream effects relevant to MASLD progression is presented in Table 1[17-24]. This includes mechanistic insight into FXR, TGR5, VDR, sphingosine-1-phosphate receptor 2 (S1PR2), CAR, and others, detailing their specific roles in lipid metabolism, inflammation, fibrosis, and insulin signaling.

Table 1 Bile acid receptors, ligands, and their roles in metabolic dysfunction-associated steatotic liver disease pathogenesis.

Receptor/pathway	Ligand/activation	Physiological role/effect	Role in MASLD/MASH
FXR[17]	CDCA, FXR agonists	↓SREBP-1c, ↑LDLR to ↓lipid accumulation; ↓NF-κB to ↓inflammation; ↑FGF19 to ↓gluconeogenesis	Central therapeutic target: Reduces steatosis, enhances insulin sensitivity, and attenuates fibrosis
CAR[18,19]	Bile acids, indirect nuclear activation	Activates Nrf2 to ↓inflammation	Supports anti-inflammatory balance via Nrf2 signaling
PXR[19]	Bile acids, xenobiotics	↓INSR signaling to ↓insulin sensitivity	Detrimental: Worsens insulin resistance and metabolic dysfunction
VDR[13]	Secondary bile acids	↓COL1α1 to ↓fibrosis	Antifibrotic potential via inhibition of extracellular matrix remodeling
TGR5 (liver)[20]	Secondary bile acids	↑AMPK to ↑energy metabolism	Improves hepatic energy metabolism and reduces inflammation
TGR5 (intestine)[20,21]	Secondary bile acids	↑GLP-1 secretion to ↑insulin sensitivity	Enhances incretin response, improving metabolic control
S1PR2[22]	CDCA	Activates PI3K-AKT to ↑insulin sensitivity	Supports insulin signaling and glucose regulation
CDCA[23]	Endogenous bile acid	Activates PI3K-AKT to ↑insulin sensitivity	Therapeutically favorable: Improves metabolic flexibility
LCA[24]	Lithocholic acid	Activates TLR4/MAPK to ↑inflammation	Pro-inflammatory: Promotes progression to MASH
NTCP/BSEP[24]	Conjugated bile acids (e.g., taurocholate)	BSEP: Exports bile acids to bile; NTCP: Reabsorbs bile acids from portal circulation	Maintains bile acid pool and facilitates enterohepatic cycling
OSTα/OSTβ/ASBT[24]	Bile acid transporters	ASBT: Intestinal bile acid uptake; OSTα/β: Efflux to portal vein	Regulate enterohepatic recirculation, essential for gut-liver axis signaling

FXR: Farnesoid X receptor; CAR: Constitutive androstane receptor; PXR: Pregnane X receptor; VDR: Vitamin D receptor; TGR5: Takeda G-protein-coupled receptor 5; S1PR2: Sphingosine-1-phosphate receptor 2; CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; NTCP: Sodium taurocholate cotransporting polypeptide; BSEP: Bile salt export pump; OST: Organic solute transporters; ASBT: Apical sodium-dependent bile acid transporter; SREBP-1c: Sterol regulatory element-binding protein 1c; LDLR: Low-density lipoprotein receptor; NF-κB: Nuclear factor kappa B; FGF19: Fibroblast growth factor 19; Nrf2: Nuclear factor erythroid-2-related factor 2; INSR: Insulin receptor; COL1α1: Collagen type I alpha 1 chain; AMPK: AMP-activated protein kinase; GLP-1: Glucagon-like peptide-1; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; TLR4: Toll-like receptor 4; MAPK: Mitogen-activated protein kinase; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis.

PHARMACOLOGICAL MODULATION OF BILE ACID SIGNALING IN MASLD: CURRENT AND EMERGING THERAPIES

The pathophysiological basis of MASLD, and particularly its progressive subtype MASH, includes profound disturbances in bile acid metabolism and signaling. Pharmacologic targeting of bile acid receptors - especially FXR, TGR5, PXR, and others - has emerged as a compelling therapeutic approach in MASLD (Table 2). These agents aim to restore metabolic homeostasis, suppress hepatic inflammation, and attenuate fibrotic progression by recalibrating disrupted bile acid-receptor interactions. However, the translation of these mechanistic benefits into long-term clinical outcomes remains an area of active investigation and debate.

Table 2 Summary of pharmacologic agents targeting bile acid signaling in metabolic dysfunction-associated steatotic liver disease pathogenesis.

Agent	Target receptor(s)	Mechanism of action	Reported efficacy	Adverse effects
OCA[25,27]	FXR	Potent FXR agonist; suppresses CYP7A1, induces FGF19, reduces lipogenesis and inflammation	Improved fibrosis stage in approximately 23% of patients without NASH worsening; ↓ALT and ballooning in NASH patients	Pruritus (up to 51%), ↑LDL-C levels
Tropifexor[39]	FXR	Non-steroidal FXR agonist; improved selectivity and tolerability	↓ALT and GGT, improved liver fat content (MRI-PDFF); significant reduction in hepatic steatosis	Pruritus (dose-dependent), mild GI symptoms
Cilofexor[29,30]	FXR	Non-steroidal FXR agonist with moderate systemic activity	Modest in ↓ALT and liver fat; greater effects in combination therapy (e.g., with firsocostat or selonsertib)	Pruritus, fatigue, mild ↑LDL-C
MET409[40]	FXR	Non-bile acid FXR agonist with liver targeting	↓ALT and steatosis; improved insulin sensitivity; less lipid disruption than OCA	GI-related adverse effects, mild pruritus
INT-767[41,42]	FXR/TGR5	Dual agonist; activates FXR and TGR5 to anti-inflammatory, insulin-sensitizing, and lipid-lowering effects	In rodent models: ↓Steatosis, ↓fibrosis, ↑GLP-1 secretion, improved insulin resistance	Potential gallbladder issues due to TGR5 activation
norUDCA[43]	Non-receptor (cholehepatic shunting)	Side-chain-shortened UDCA; induces bicarbonate-rich choleresis; anti-fibrotic and anti-inflammatory without FXR activation	↓Hepatic inflammation, ↓TGF-β1 signaling, ↓collagen deposition in MASLD models	Well, tolerated; minimal pruritus, no LDL elevation
BAR502[44]	FXR/TGR5	Dual agonist; enhances bile acid-FGF19 axis and GLP-1 signaling	↓Steatosis and fibrosis in animal models; improved insulin sensitivity	Under investigation
PXL065[45,46]	Mitochondrial PD modulator (PPAR-sparing TZD derivative)	Anti-inflammatory and insulin-sensitizing via mitochondrial bioenergetics modulation	↓ALT, improved hepatic fat content in MASLD	Reduced edema compared to pioglitazone
ASC42[46,47]	FXR	Potent oral FXR agonist with high liver selectivity	Preclinical studies show reduction in hepatic steatosis and inflammation	Data limited

OCA: Obeticholic acid; norUDCA: Norursodeoxycholic acid; FXR: Farnesoid X receptor; TGR5: Takeda G-protein-coupled receptor 5; PD: Protonophoric decoupling; PPAR: Peroxisome proliferator-activated receptor; TZD: Thiazolidinedione; CYP7A1: Cholesterol 7α-hydroxylase; FGF19: Fibroblast growth factor 19; UDCA: Ursodeoxycholic acid; GLP-1: Glucagon-like peptide-1; ALT: Alanine aminotransferase; NASH: Nonalcoholic steatohepatitis; GGT: Gamma-glutamyl transferase; MRI: Magnetic resonance imaging; PDFF: Proton density fat fraction; TGF: Transforming growth factor; MASLD: Metabolic dysfunction-associated steatotic liver disease; LDL-C: Low-density lipoprotein cholesterol; GI: Gastrointestinal; LDL: Low-density lipoprotein.

FXR agonists

FXR agonism represents the most clinically advanced and mechanistically validated strategy in bile acid-based therapeutics for MASLD. OCA, a semi-synthetic derivative of CDCA, is the first FXR agonist to progress into late-stage clinical development. In pivotal trials such as REGENERATE[25] and FLINT[26], OCA demonstrated significant antifibrotic efficacy, with a notable proportion of patients achieving ≥ 1-stage fibrosis improvement without worsening of MASH.

Mechanistically, OCA activates FXR in both hepatocytes and ileal enterocytes, initiating a feedback cascade through SHP to suppress CYP7A1 and inhibit bile acid synthesis. Concurrently, OCA induces FGF19 in the intestine, which exerts endocrine effects on the liver by downregulating gluconeogenesis, de novo lipogenesis, and inflammatory mediators such as NF-κB[27]. These pathways converge to reduce hepatic steatosis, improve insulin sensitivity, and attenuate fibrogenic signaling.

Despite its therapeutic promise, the clinical utility of OCA has been tempered by dose-dependent adverse effects. Pruritus, occurring in up to 51% of patients at higher doses, and elevations in low-density lipoprotein cholesterol (LDL-C) are key concerns. The observed increase in LDL-C has raised questions regarding potential long-term cardiovascular risk, particularly in a population already burdened by cardiometabolic comorbidities. In response, second-generation non-steroidal FXR agonists - including tropifexor (LJN452), cilofexor (GS-9674), and metacrine (MET409) - have been developed with improved pharmacokinetic and pharmacodynamic profiles[28]. These agents demonstrate greater receptor selectivity, reduced off-target lipid effects, and favorable tolerability in early-phase trials.

Cilofexor (GS-9674) is a nonsteroidal FXR agonist developed for cholestatic liver disease and MASH. It has shown consistent effects on bile-acid metabolism, liver enzymes, and liver fat in phase II studies, and when combined with complementary agents (firsocostat, semaglutide, etc.) produced larger effects on NASH activity and some signals for antifibrotic benefit in patients with advanced disease[29,30]. Safety signals have been manageable in trials (dose-related pruritus is the most common adverse effect). Extended follow-up and ongoing phase 3 and combination programs are expected to clarify the durability of histologic benefit and the long-term metabolic and cardiovascular safety profile of cilofexor-based regimens.

Moreover, preclinical data from murine models of MASH further supports their utility, demonstrating reduction in hepatic inflammation and fibrosis via suppression of hepatic stellate cell activation, restoration of gut barrier integrity, and modulation of the gut-liver immune axis[31]. While FXR-targeted therapies represent a cornerstone of bile acid-based intervention in MASLD, their ultimate clinical positioning will depend on long-term efficacy and safety outcomes from ongoing and extended clinical evaluations.

norUDCA

norUDCA is a side-chain-shortened homologue of ursodeoxycholic acid, distinguished by its unique mechanism of cholehepatic shunting, which enables it to undergo repeated circulation between hepatocytes and cholangiocytes without requiring active transporters or conjugation. Unlike FXR agonists, norUDCA acts via FXR-independent mechanisms, making it a particularly attractive option for patient’s intolerant or unresponsive to FXR-based therapies[32].

Pharmacodynamically, norUDCA induces bicarbonate-rich hypercholeresis, enhancing bile flow and diluting toxic hydrophobic bile acids. It exerts anti-inflammatory and anti-fibrotic effects through downregulation of proinflammatory cytokines and inhibition of TGF-β1-mediated hepatic stellate cell activation. Additionally, norUDCA reduces oxidative stress, improves mitochondrial function, and attenuates portal pressure - attributes that contribute to its broad hepatoprotective actions[33,34]. Importantly, norUDCA maintains a favorable lipid profile, does not raise LDL-C levels, and is well tolerated, with a substantially lower incidence of pruritus compared to FXR agonists[33,34].

Clinical efficacy of norUDCA in MASLD was highlighted in a randomized, double-blind, placebo-controlled, phase 2 dose-finding multicenter trial conducted across Austria and Germany, in which 198 patients with non-alcoholic fatty liver disease, including those with T2D, were randomized to receive 500 mg/day or 1500 mg/day of norUDCA or placebo for 12 weeks. The study demonstrated a significant, dose-dependent reduction in serum alanine aminotransferase, with the 1500 mg group showing a mean change of -27.8% from baseline. Additionally, norUDCA was associated with a favorable safety profile, with adverse events being mild and comparable across all groups and no observed LDL-C elevation[35]. Nevertheless, confirmation of long-term antifibrotic efficacy and clinical outcome benefit will require data from ongoing longer-duration studies.

TGR5 agonists and dual FXR/TGR5 agonists

TGR5 is a bile acid-activated G protein-coupled receptor that enhances GLP-1 secretion, promotes energy expenditure, and attenuates hepatic inflammation[7]. While selective TGR5 agonists remain largely preclinical due to concerns over gallbladder hypertrophy, dual FXR/TGR5 agonists such as INT-767 have demonstrated synergistic efficacy in experimental models. INT-767 improves steatosis, insulin sensitivity, and fibrosis in murine MASLD models by activating both FXR-mediated SHP-FGF19 signaling and TGR5-driven cAMP/protein kinase A pathways[36]. However, the long-term safety and clinical translatability of dual receptor activation strategies remain to be established.

PXR, CAR, and S1PR2 modulators

Although FXR and TGR5 dominate therapeutic exploration, other bile acid sensors are increasingly studied. PXR activation may impair insulin signaling and exacerbate lipid accumulation[37], whereas CAR appears to act synergistically with FXR to reduce steatosis and inflammation[19,38]. S1PR2, activated by conjugated bile acids, is implicated in hepatic stellate cell activation and fibrogenesis in MASH[22]. These pathways may represent adjunctive targets in selected MASLD phenotypes, although their clinical relevance remains incompletely defined. A comprehensive summary of pharmacologic agents targeting bile acid signaling in MASLD in Table 2[25,27,29,30,39-47].

Challenges and considerations

Despite promising mechanistic and preclinical evidence, several challenges hinder translation, including adverse effects such as pruritus, inter-individual variability in response, and uncertainty regarding long-term safety - particularly for FXR agonists and dual-receptor modulators. Importantly, concerns regarding lipid profile alterations and potential cardiovascular risk, as well as the durability of histologic benefit, underscore the need for continued follow-up of ongoing clinical programs and cautious interpretation of current trial data. Thus, precision therapeutics targeting the right receptor in the right patient and at the right disease stage remains essential.

GUT MICROBIOTA AND BILE ACID CROSS-TALK IN MASLD

The gut microbiota exerts a profound influence on host metabolism, immunity, and liver health via its role in bile acid transformation. This dynamic interplay - referred to as the gut microbiota-bile acid axis - is increasingly recognized as central to the pathogenesis and progression of MASLD. Alterations in gut microbial composition represent an upstream event that can reshape bile acid metabolism, disrupt receptor-mediated signaling, and ultimately contribute to hepatic inflammation and fibrosis. Microbial dysbiosis disrupts bile acid composition and receptor-mediated signaling, amplifying metabolic dysfunction, hepatic inflammation, and fibrosis[48].

Microbial enzymatic transformation of bile acids

Primary bile acids synthesized in hepatocytes (mainly CA and CDCA) are secreted into the intestine and undergo extensive microbial biotransformation. Enzymes such as bile salt hydrolases (BSHs) catalyze the deconjugation of taurine- and glycine-conjugated bile acids, while 7α-dehydroxylases convert primary into secondary bile acids - including deoxycholic acid (DCA) from CA and LCA from CDCA (Figure 1). Through these deconjugation and transformation processes, the gut microbiota directly determines the size, composition, and physicochemical properties of the bile acid pool.

These modifications not only alter bile acid solubility and toxicity but also significantly impact their receptor-binding affinities. Notably, secondary bile acids such as LCA and DCA are strong TGR5 agonists but weaker FXR agonists, whereas primary bile acids, particularly CDCA, are potent FXR activators. Accordingly, changes in microbial bile acid-transforming capacity can shift the balance between FXR and TGR5 activation, a key determinant of hepatic lipid metabolism, inflammation, and fibrogenesis[49].

Dysbiosis and impaired bile acid receptor signaling in MASLD

In MASLD, patients typically exhibit a gut microbial profile characterized by reduced diversity and depletion of key bile acid-modifying bacteria (e.g., Clostridium, Bacteroides, Lactobacillus)[50]. These microbial alterations precede and drive changes in bile acid composition, resulting in: (1) Reduced conversion of primary to secondary bile acids; (2) Altered FXR and TGR5 activation patterns; (3) Accumulation of hepatotoxic or pro-inflammatory bile acid species (e.g., DCA, LCA); and (4) Enhanced intestinal permeability and endotoxin leakage into portal circulation.

As a consequence of altered bile acid signaling, intestinal FXR-FGF19 feedback is impaired, leading to increased CYP7A1 activity, elevated hepatic bile acid synthesis, and worsening steatosis. Simultaneously, insufficient or dysregulated TGR5 activation reduces GLP-1 secretion, energy expenditure, and anti-inflammatory signaling, thereby promoting insulin resistance and hepatic inflammation[49,50].

Moreover, secondary bile acids such as LCA and DCA can activate toll-like receptor 4 and mitogen-activated protein kinase pathways, promoting NF-κB-mediated cytokine production and fibrogenesis. Thus, microbial-driven bile acid alterations provide a mechanistic link between dysbiosis and downstream inflammatory and fibrotic liver injury. Conversely, protective receptors such as FXR and VDR are downregulated in dysbiosis, further tilting the metabolic environment toward progression from simple steatosis to MASH[51,52].

Therapeutic implications: Targeting the microbiota-bile acid axis

The centrality of the gut microbiota-bile acid axis in MASLD has catalyzed interest in microbiota-modulating interventions, including probiotics and prebiotics that restore BSH-producing taxa, fecal microbiota transplantation, BSH-targeted strategies, and bile acid sequestrants. These approaches aim to correct upstream microbial disturbances, normalize bile acid composition, and restore disbalanced FXR and TGR5 signaling.

Additionally, co-administration of bile acid receptor agonists (e.g., OCA or INT-767) with microbiome-targeted therapies may synergistically improve bile acid signaling and metabolic outcomes[53]. Such strategies conceptually link microbial modulation to receptor-level correction and downstream hepatic benefit.

Disruption of the gut microbiota-bile acid axis is a defining feature of MASLD progression, driving metabolic imbalance, impaired receptor signaling, and hepatic inflammation. By clarifying the causal sequence from microbial dysbiosis to bile acid alteration, receptor dysfunction, and liver injury, this axis emerges as a coherent and biologically plausible therapeutic target in MASLD (Table 3).

Table 3 Microbial enzymes, bile acid transformations, and receptor-mediated effects in metabolic dysfunction-associated steatotic liver disease pathogenesis[53,54].

Microbial enzyme	Bile acid transformation	Key products	Receptor binding	Pathophysiological effects in MASLD
BSH	Deconjugation of taurine/glycine-conjugated BAs	Free primary BAs (e.g., CA, CDCA)	↑FXR (CDCA) ↓TGR5	Facilitates FXR activation in ileum to ↑FGF19 to ↓BA synthesis; however, dysregulation may lead to FXR desensitization
7α-dehydroxylase	Removal of 7α-hydroxyl group from primary BAs	DCA (from CA), LCA (from CDCA)	↑TGR5 ↓FXR (weak agonists)	↑GLP-1, ↑energy expenditure (via TGR5); ↑pro-inflammatory signaling (via TLR4, MAPK); ↓intestinal FXR signaling
HSDH	Epimerization and oxidation of hydroxyl groups	Iso- and oxo-BA forms	Varies (limited data)	May alter BA pool toxicity and gut-liver signaling; epimers often show reduced receptor affinity
Sulfatases	Desulfation of secondary bile acids	Unconjugated secondary BAs	↑TGR5	Increases bioavailability of TGR5 agonists (e.g., LCA) to promotes anti-inflammatory and metabolic signaling
Dehydrogenases and reductases	Oxidation-reduction reactions of hydroxyl/keto groups	Oxo-bile acids, dehydro forms	↓FXR (typically weak)	May lead to accumulation of hepatotoxic bile acid species to ↑oxidative stress and inflammation

BSH: Bile salt hydrolase; HSDH: Hydroxysteroid dehydrogenase; BA: Bile acid; CA: Cholic acid; CDCA: Chenodeoxycholic acid; DCA: Deoxycholic acid; LCA: Lithocholic acid; FXR: Farnesoid X Receptor; TGR5: Takeda G Protein-Coupled Receptor 5; FGF19: Fibroblast growth factor 19; TLR4: Toll-like receptor 4; MAPK: Mitogen-activated protein kinase; MASLD: Metabolic dysfunction-associated steatotic liver disease.

FUTURE IMPLICATIONS

In light of the limitations observed with single-pathway modulation and the variability in receptor responsiveness and safety profiles discussed above, emerging therapeutic strategies such as dual receptor agonists and tissue-selective agents have been proposed. These approaches remain largely conceptual and investigational, aiming to address unresolved challenges in efficacy, tolerability, and long-term safety.

The integration of bile acid signaling modulation into the clinical management of MASLD represents a transformative shift from conventional metabolic and hepatocellular-targeted therapies to hormonal and immune-metabolic interventions. As the understanding of the bile acid-receptor-microbiota axis deepens, this pathway is emerging as a central hub for multi-organ crosstalk, with direct relevance to hepatic lipid metabolism, insulin sensitivity, inflammation, and fibrosis[53,54].

Many promising agents are being explored as adjuvant or combination therapies to restore a healthier bile acid profile and enhance receptor responsiveness[55,56]: (1) Dual and multi-receptor agonists: Development of agents targeting FXR, TGR5, VDR, and CAR concurrently to achieve comprehensive metabolic and anti-inflammatory effects with potential dose-sparing synergy; (2) Tissue-selective agonists: Next-generation molecules that activate bile acid receptors selectively in the intestine (e.g., to favor FGF19 production without systemic FXR overload) or adipose tissue (for energy regulation) may enhance efficacy while minimizing toxicity; and (3) Combination regimens: Co-treatment with FXR agonists and acetyl-CoA carboxylase inhibitors - such as firsocostat, which inhibits acetyl-CoA carboxylase, the rate-limiting enzyme in de novo lipogenesis, GLP-1 receptor agonists, and metformin or sodium-glucose cotransporter 2 inhibitors. These combination strategies are intended to target multiple pathogenic mechanisms underlying MASLD, although their optimal clinical positioning remains to be determined.

Integration of serum bile acid profiling, microbiota sequencing, and genetic polymorphism analysis (e.g., nuclear receptor subfamily 1 group H member 4 variants) may facilitate personalized treatment paradigms that align with individual receptor activity, microbiota configuration, and disease stage. Furthermore, the development of non-invasive biomarkers to monitor therapeutic response - such as FGF19 levels, bile acid ratios, or microbiota-derived metabolites - will be critical for widespread clinical adoption and regulatory approval.

CONCLUSION

The pharmacologic manipulation of bile acid pathways offers an exciting and mechanistically grounded frontier in MASLD therapy, with the potential to influence not only liver histology but also systemic metabolic risk and gut-liver homeostasis. However, the clinical translation of these mechanistic advances remains influenced by disease stage, inter-individual variability, and unresolved safety considerations. Ongoing clinical trials, molecular phenotyping efforts, and microbiome-based therapeutic strategies are expected to clarify the long-term efficacy, safety, and optimal positioning of bile acid-targeted interventions, thereby contributing to a more precise, personalized, and pathway-convergent treatment landscape for MASLD.