PERK drives aflatoxin B1-induced chicken cellular senescence by promoting NLRP3-mediated PANoptosis

INTRODUCTION: Mycotoxins are ubiquitous pollutants that can pose a serious threat to public health. Aflatoxin B1 (AFB1), one of the most toxic mycotoxins, is potentially hazardous to humans and animals. Poultry is more sensitive to AFB1 toxicity, and the principal target organ for AFB1 is the liver. However, the specific molecular mechanism by which AFB1 induces chicken hepatocyte injury remains unclear. OBJECTIVES: This study aims to explore the role of PERK in AFB1-induced hepatocellular injury and its relation with PANoptosis in chicken. METHODS: We established both in vivo and in vitro models to investigate the effects of AFB1 on liver damage. Histological analysis and ultrastructure observation were employed to observe hepatic tissue and ultrastructural changes. Western blotting, and immunofluorescence assays were used to detect the expression of markers related to ER stress, inflammatory responses, PANoptosis, and cellular senescence. RESULTS: AFB1 induced hepatic histopathological damage and enhanced appearance of swollen endoplasmic reticulum (ER). We found that AFB1 targeted and upregulated expression of PERK protein, resulting in eIF2α phosphorylation and thus activating ER stress. In addition, AFB1 upregulated the expression of PANoptosis-related signal molecules, which is accompanied by NLRP3 inflammasome activation and amplified the inflammatory response. AFB1 also promoted cellular senescence in chicken hepatocytes. Of note, PERK knockdown mitigated AFB1-induced cellular senescence by suppressing NLRP3-mediated PANoptosis. CONCLUSION: This study demonstrates that AFB1 induces endoplasmic reticulum stress by upregulating PERK expression, thereby activating the NLRP3 inflammasome to trigger PANoptosis, promoting cellular senescence and ultimately contributing to hepatotoxicity. These findings provide evidence for the role of PERK in mycotoxin-induced chicken hepatocytes damage and point to PERK as a potential therapeutic target for treatment of liver diseases.