Imeglimin attenuates liver fibrosis by inhibiting vesicular ATP release from hepatic stellate cells.

Abstract

The protective effects of imeglimin, a recently approved antidiabetic agent, against liver fibrosis have not been previously evaluated. In this study, we demonstrated that 8-week administration of imeglimin attenuated immune cell infiltration and reduced collagen deposition, improving fibrosis stage in a thioacetamide-induced murine model. Further analyses focusing on hepatic stellate cells (HSCs), the primary effector cells in fibrogenesis, revealed decreased expression of α-smooth muscle actin and desmin, markers of HSC activation. Mechanistically, a clinically relevant low concentration (10 μm) of imeglimin reduced intracellular vesicular ATP accumulation and subsequently suppressed ATP release from HSCs in vitro. These findings suggest that imeglimin may exert anti-inflammatory and antifibrotic effects by inhibiting vesicular ATP release and ATP-mediated purinergic signaling. Impact statement At clinically relevant doses, imeglimin inhibits vesicular ATP release from hepatic stellate cells, reducing inflammatory infiltration and fibrotic collagen accumulation. These findings support its evaluation as a combined metabolic and antifibrotic therapy for MASLD and other chronic liver conditions.