Asiaticoside ameliorates pyrimethanil-induced autophagy-dependent liver injury by suppressing CRHR1.

Pyrimethanil is a widely used fungicide that accumulates in the food chain and poses potential health risks, yet the mechanisms underlying its chronic hepatotoxicity remain poorly understood. Here, we demonstrate that pyrimethanil induces liver injury in zebrafish and mouse models by directly binding to and activating corticotropin-releasing hormone receptor 1 (CRHR1), without altering its expression. CRHR1 activation triggers excessive autophagy-characterized by elevated LC3-II accumulation and upregulation of autophagy-related genes-leading to hepatocyte apoptosis and subsequent hepatic inflammation. In a compound screen, the natural triterpenoid Asiaticoside effectively mitigated pyrimethanil-induced liver injury. Mechanistically, Asiaticoside downregulated CRHR1 expression, thereby suppressing excessive autophagy and blocking the apoptosis-inflammation cascade. Our study reveals a novel CRHR1-dependent autophagy pathway in pyrimethanil-induced hepatotoxicity and identifies Asiaticoside as a promising therapeutic candidate for pesticide-related liver injury.