Mycotoxin Alternariol exposure promotes endoplasmic reticulum stress-induced hepatotoxicity to exacerbate chronic liver injury.

As a mycotoxin ubiquitously detected in global food supplies, Alternariol (AOH) has garnered significant attention due to its documented health risks. However, hepatotoxic effect of chronic exposure to AOH at environmental levels remains poorly characterized. Herein, we aim to investigate the long-term effects of dietary AOH exposure on murine liver and key signaling event through integrated in vivo and in vitro models. AOH exposure significantly induced dose-dependent hepatopathy characterized by liver injury, inflammatory cell infiltration, and liver fibrosis. RNA-sequencing analyses further indicated that the pivotal molecular mechanism linking the hepatotoxic effect of AOH were endoplasmic reticulum (ER) stress-mediated apoptosis via PERK/ATF4/CHOP signaling cascade. In vitro models confirmed AOH promoted the PERK/ATF4/CHOP signaling activation and subsequent apoptosis in primary murine hepatocytes and human hepatocyte cell line THLE-2. Pharmacological intervention studies demonstrated that both TUDCA (ER stress inhibitor) and GSK2606414 (PERK inhibitor) effectively mitigated AOH-induced cytotoxicity in hepatocytes. Notably, TUDCA administration demonstrated therapeutic efficacy in mitigating AOH-induced hepatic pathology in mice. Thus, we delineate ER stress as central mechanism driving AOH-induced hepatotoxicity and validate PERK cascade inhibition as viable protective strategy. These findings fundamentally refine risk assessment framework for mycotoxin exposure while proposing novel molecular targets for therapeutic intervention against environmental hepatotoxicants.