Cuproptosis in atrazine-induced hepatotoxicity: ATOX1 as a therapeutic target for lycopene-mediated protection

Introduction Atrazine (ATR) is a widely used herbicide in agriculture, and its residues pose a threat to biological organs, with particularly severe damage to the liver. Lycopene (LYC) is a natural pigment that exhibits beneficial effects on health, particularly liver health. However, the mechanism by which LYC mitigates liver injury induced by ATR remains unclear, and the hepatotoxicity induced by ATR requires further investigation. Objectives This study aimed to investigate cuproptosis involvement in ATR hepatotoxicity and elucidate the protective mechanisms of LYC. Methods We established both chicken animal models and cell models to investigate the effects of LYC on ATR-induced liver injury. A variety of experimental approaches were utilized to evaluate the impacts of LYC and ATR on hepatic tissue damage, mitochondrial dysfunction, oxidative stress, and markers associated with cuproptosis. Results ATR exposure was associated with increased copper ion accumulation and oxidative stress markers, along with decreased antioxidant enzyme activities. Severe liver damage and mitochondrial dysfunction were observed in ATR-treated groups through histopathological analysis, and these effects were alleviated by LYC. Mechanistic studies revealed that ATR induced the expression of cuproptosis-related proteins and metabolic markers, indicating activation of cuproptosis pathways. These effects were mitigated by LYC treatment. Strong binding affinity between LYC and ATOX1 was revealed by molecular docking. ATR-induced cuproptosis was significantly inhibited by ATOX1 knockdown, confirming its critical role. Conclusion Overall, it was determined that ATOX1-mediated cuproptosis is involved in ATR-induced liver toxicity and the therapeutic effects of LYC. The findings enrich the understanding of the pathogenesis of ATR-induced liver toxicity and provide data to support further cuproptosis studies.