Pollutant retrorsine induces hepatotoxicity through ATF3-mediated ferroptosis in mouse primary hepatocytes and Cyp3a4-HepG2 cells

Pyrrolizidine alkaloid (PA) contamination in food poses a global health risk, primarily entering the human food chain through contaminated food. Given that ferroptosis—a form of cell death characterized by glutathione depletion—is involved in toxicant-induced liver injury and that retrorsine (RTS, A typical toxic PA) depletes glutathione, we investigated whether RTS induces hepatotoxicity via ferroptosis. This study demonstrates that RTS induces acute hepatotoxicity and ferroptosis in vitro and in vivo, RTS triggers mitochondrial dysfunction and activates ATF3, which translocates to the nucleus to directly repress PLA2G6 expression. Genetic studies revealed ATF3's dual role in enhancing RTS-induced cytotoxicity and oxidative stress, while its target PLA2G6 confers protection, unveiling a novel mechanism of RTS-induced liver injury centered on the ATF3-PLA2G6 axis. These findings demonstrates that RTS-induced hepatotoxicity, driven by ferroptosis, is governed by the ATF3-PLA2G6 axis, thus revealing a pivotal mechanism and a promising therapeutic target for PA-related liver injury. Overall design: We set up control group (NaCl group), retrorsine 25mg/kg group, and 50mg/kg group, three repetitions per group, and collected mouse liver samples for RNA seq after intraperitoneal injection 2 hours.