Downregulation of LANCL1 exacerbates jaundice-induced liver injury by enhancing oxidative stress and hepatocyte apoptosis.

Obstructive jaundice (OJ) is a major cause of hepatic injury, yet its underlying molecular mechanisms remain incompletely understood. Through proteomic analysis of serum from OJ children, we identified a significant downregulation of Lanthionine synthetase C-like protein 1 (LANCL1). To investigate its functional role, we employed an in vivo model of bile duct ligation (BDL) and an in vitro model using BDL serum-treated BRL-3A hepatocytes. Western blotting confirmed the suppression of LANCL1 in both models. Overexpression of LANCL1 was performed to assess its protective effects. Liver injury was evaluated via H&E staining, serum biomarkers (ALT, AST, TBIL), and hepatocyte apoptosis rates. Oxidative stress was measured in vitro (MitoSOX, MDA, SOD) and in vivo (ATP, MDA, SOD, mtDNA). The downstream LANCL1-SIRT3-SOD2 pathway was analyzed by assessing SIRT3 expression and SOD2 deacetylation. Our results demonstrate that OJ-induced downregulation of LanCL1 inhibits the SIRT3-mediated deacetylation of SOD2, thereby impairing antioxidant capacity. This leads to increased oxidative stress and hepatocyte apoptosis, culminating in liver injury. Importantly, LANCL1 overexpression mitigated these pathological changes, attenuating oxidative stress, apoptosis, and histological damage. In conclusion, the LANCL1-SIRT3-SOD2 axis plays a crucial role in OJ-induced hepatotoxicity, and these findings identify LANCL1 as a novel key regulator of OJ-induced liver injury, providing a foundational basis for the development of targeted therapeutic interventions.