RIPK3/MLKL-mediated necroptosis promotes hepatic inflammation in chronic arsenic exposure through drinking water.

Chronic exposure to arsenic-contaminated drinking water is a major environmental risk factor for liver injury, yet its pathogenic mechanisms remain unclear. This study explores the role of RIPK3/MLKL-mediated necroptosis in arsenic-induced hepatotoxicity using a chronic in vivo mouse model. Mice were exposed to sodium arsenite (NaAsO2) at concentrations of 2.8, 8.4, and 25.2 mg/L in drinking water for 8 weeks. Arsenic exposure induced dose-dependent hepatocellular necrosis, elevated liver injury markers (ALT, AST, GST-α, GDH), and increased hepatic expression of p-RIPK3, p-MLKL and HMGB1, along with upregulation of the proinflammatory cytokines TNF-α and IL-6. Notably, Mlkl-/- mice exhibited significantly reduced liver injury and lower levels of ALT, AST, GSHα, and GDH, decreased HMGB1, TNF-α and IL-6 expression, following high-dose arsenic exposure (25.2 mg/L) compared to WT controls. These findings indicate that RIPK3/MLKL-mediated necroptosis contributes to arsenic-induced liver injury by promoting hepatocyte death and inflammation. Inhibiting MLKL alleviates arsenic-induced liver injury by reducing cell death and inflammation in mice. Targeting MLKL may offer a promising therapeutic approach for mitigating chronic arsenic-related hepatotoxicity.