Atractylenolide I ameliorates acute-on-chronic liver failure (ACLF) by promoting autophagy and preserving mitochondrial function through mTOR inhibition.

Abstract

Acute-on-chronic liver failure (ACLF) is a severe liver syndrome marked by systemic inflammation and high mortality, often complicated by autophagy impairment and mitochondrial dysfunction. This study investigates atractylenolide I (AT-1), a compound from Atractylodes macrocephala, for its potential to mitigate ACLF through modulation of mammalian target of rapamycin (mTOR) signaling, autophagy, and mitochondrial integrity. We hypothesized that AT-1 could attenuate ACLF-induced liver damage by enhancing autophagy and mitochondrial function. A rat ACLF model which combining chronic liver injury induced by repeated bovine serum + Freund's adjuvant injections with an acute hepatic insult using lipopolysaccharide (LPS) and D-Galactosamine (D-GalN) and LPS-induced BRL 3 A liver cell line were treated with AT-1, with or without mTOR activator MHY1485. In vivo, AT-1 reduced liver fibrosis, inflammation, necrosis, and ALT/AST levels in ACLF rats, while improved autophagy proteins. In vitro, AT-1 enhanced cell viability, decreased apoptosis, and restored autophagic flux and mitochondrial health. The addition of MHY1485 partially reversed these benefits, suggesting the protective effects of AT-1 depend on mTOR inhibition. These findings propose AT-1 as a therapeutic candidate for ACLF by modulating autophagy and mitochondrial function.