Dantrolene attenuates steatohepatitis and liver fibrosis by suppressing Ca2+ dysregulation.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by steatosis, inflammation, and fibrosis; however, effective pharmacological therapies targeting fibrogenesis remain limited. Increasing evidence suggests that dysregulation of intracellular calcium (Ca2+) signaling contributes to hepatic injury and stellate cell activation. In this study, we investigated whether pharmacological suppression of Ca2+ dysregulation by dantrolene, a ryanodine receptor inhibitor, ameliorates steatohepatitis and liver fibrosis. A choline-deficient l-amino acid-defined (CDAA) diet-induced MASH rat model was used to evaluate the in vivo effects of dantrolene. Dantrolene treatment did not affect liver enlargement but partially improved serum markers of hepatocellular injury. Histological analyses revealed marked attenuation of hepatic fibrosis and a significant reduction in glutathione S-transferase π-positive preneoplastic lesions. At the cellular level, dantrolene suppressed free fatty acid-induced lipid accumulation in primary hepatocytes. Furthermore, in human hepatic stellate cells (LX-2), dantrolene markedly inhibited transforming growth factor-β-induced collagen type I expression. Live-cell Ca2+ imaging demonstrated that dantrolene significantly attenuated pathological intracellular Ca2+ elevation associated with stellate cell activation. These findings indicate that Ca2+ dysregulation plays a central role in the pathogenesis of MASH and that targeting intracellular Ca2+ signaling with dantrolene effectively suppresses steatohepatitis and liver fibrosis. Pharmacological modulation of Ca2+ homeostasis may represent a promising and translatable therapeutic strategy for MASH.