Obeticholic acid exacerbates liver injury through hepatocyte-mediated release of HMGB1 by inducing lysosomal membrane permeabilization in cholestasis.

Obeticholic acid (OCA), a therapy for primary biliary cholangitis (PBC) unresponsive to ursodeoxycholic acid (UDCA), poses risks of hepatotoxicity that may worsen liver failure and increase mortality. Safety studies regarding OCA are imperative for guiding clinical practice. High-mobility group box 1 (HMGB1), an extracellular damage-associated molecular pattern molecule implicated in various liver pathologies, was mechanistically examined in the context of OCA-induced liver injury. In bile duct ligation (BDL) mice, OCA (40 mg/kg) administration significantly elevated serum and cytoplasmic levels of HMGB1, correlating with an exacerbated ductular reaction, necrosis, and liver fibrosis. Pharmacological inhibition of HMGB1 using ethyl pyruvate alleviated these pathological features. In vitro, OCA (100 μM) stimulated the release of HMGB1 (∼100 pg/mL) from primary hepatocyte supernatants. Mechanistic studies revealed that OCA-induced lysosomal membrane permeabilization triggered the leakage of cytosolic acid proteases, which prevented the autophagic degradation of cytoplasmic HMGB1 and promoted its subsequent extracellular release. These findings demonstrate that OCA-induced hepatocyte cell death occurs through lysosomal membrane permeabilization, which subsequently leads to the release of HMGB1. This highlights HMGB1 or lysosomal function as potential therapeutic targets for mitigating OCA-associated hepatotoxicity.