Citrinin Induces Hepatic Inflammatory Injury through the PERK–CHOP–NLRP3 Axis-Mediated Pyroptosis

Citrinin (CTN), a widespread food and feed contaminant, poses a significant health risk, yet its hepatic toxicity remains unclear. Here, we investigated the role of endoplasmic reticulum (ER) stress-mediated pyroptosis in CTN-induced liver injury using mice and HL-7702 cells. CTN exposure disrupted the hepatic cord structure, induced hepatocyte swelling with karyolysis, and promoted inflammatory infiltration. Liver injury markers and pro-inflammatory cytokines IL-1β and IL-18 were significantly elevated in both models, confirming inflammatory liver injury. Mechanistically, CTN activated pyroptosis-related proteins and triggered ER stress. In HL-7702 cells, CTN-induced inflammatory injury was mediated by NLRP3-dependent pyroptosis. Silencing CHOP alleviated injury by suppressing NLRP3 activation, while selective inhibition of PERK reduced CHOP expression and further attenuated pyroptosis. Collectively, these findings demonstrate that the PERK-CHOP pathway regulates NLRP3-dependent pyroptosis, contributing to CTN-induced hepatotoxicity. The PERK-CHOP-NLRP3 axis may represent a potential therapeutic target against CTN-related liver injury.