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

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.