Taurocholic acid attenuates hepatic inflammation in MASH and modulates the PPARγ/NF-κB axis.

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease, is characterized by hepatocellular injury, inflammation, and varying degrees of fibrosis. Nevertheless, effective pharmacological treatments remain limited. Bile acids act as important signaling molecules, and disruption of bile acid homeostasis has been implicated in MASH pathogenesis. Here, we investigated whether the endogenous taurine-conjugated bile acid taurocholic acid (TCA) modulates hepatic inflammation in MASH. Network pharmacology identified 42 shared targets between TCA and MASH, including peroxisome proliferator-activated receptor γ (PPARγ), mitogen-activated protein kinase 14, mitogen-activated protein kinase 8, prostaglandin-endoperoxide synthase 2, nitric oxide synthase 3, with enrichment in peroxisome proliferator-activated receptor signaling and inflammation-related pathways. Molecular docking further suggested potential interactions between TCA and the bile acid receptors farnesoid X receptor and G protein-coupled bile acid receptor 1. In a mouse model of MASH, TCA ameliorated hepatic steatosis and inflammatory cell infiltration; reduced serum alanine aminotransferase and aspartate aminotransferase activities; decreased hepatic inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β levels; increased PPARγ abundance; and suppressed nuclear factor kappa B (NF-κB) activation. Consistently, in lipopolysaccharide-stimulated RAW264.7 macrophages, TCA reduced the production of pro-inflammatory mediators, increased PPARγ expression, and suppressed NF-κB activation. These effects were markedly attenuated by the selective PPARγ antagonist GW9662. Collectively, these findings suggest that TCA attenuates hepatic inflammation in MASH, at least in part through modulation of the PPARγ/NF-κB signaling axis. These results provide a mechanistic rationale for further investigating bile acid-based strategies targeting inflammatory pathways in MASH.