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

  • Ecotoxicol Environ Saf. 2025 Dec:308:119482. doi: 10.1016/j.ecoenv.2025.119482.
Risi Chen  1 ,  Ying Zeng  2 ,  Meixin Min  3 ,  Ke Xu  3 ,  Tingting Liu  1 ,  Jinze Ma  1 ,  Qiang Luo  1 ,  Yunxia Yang  4 ,  Dan Deng  5 ,  Yan Liu  6 ,  Xiaoping Xiao  7
Affiliations
  • 1. Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, China; Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, China.
  • 2. Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China.
  • 3. Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, China.
  • 4. College of Life Science and Technology, Gannan Normal University, Ganzhou, Jiangxi 341000, China.
  • 5. Gannan Health Vocational College, Ganzhou, Jiangxi 341000, China.
  • 6. Gannan Medical University, Ganzhou, Jiangxi 341000, China.
  • 7. Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, China; Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, China. Electronic address: [email protected].
PMID: 41338089 DOI: 10.1016/j.ecoenv.2025.119482
Abstract

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.

Keywords
Asiaticoside; Autophagy; CRHR1 receptor; Liver injury; Pyrimethanil.
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