Lycopene inhibits zearalenone-induced ferroptosis via activating AMPK/Nrf2 signaling pathway in AML-12 hepatocytes and in mice livers

作者：Chao Song, Xianghui Li, Aiguo Zhang, Kun Yang, Shuangxing Jin, Xia Ma, Yuchen Jiang, Chenfei Li, Haiyan Chen, Yuchen Wu, Fayin Tang · 发表于：Ecotoxicology and Environmental Safety · 年份：2025 · DOI：10.1016/j.ecoenv.2025.119045 · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、MicroRNA in disease regulation

Lycopene (LYC) can mitigate zearalenone (ZEA)-induced hepatotoxicity, but its effects on ferroptosis and the underlying mechanisms are unclear. This study assessed LYC's antiferroptotic effects and mechanisms using an mouse model and a cellular model stimulated with ZEA. The results showed that LYC increased cell viability and attenuated the typical morphological changes of ferroptosis in ZEA-treated AML-12 cells. Meanwhile, LYC mitigated ferroptosis hallmarks by inhibiting ferrous ion, reactive oxygen species, and lipid peroxidation levels, while increasing ferritin heavy chain 1, glutathione peroxidase 4, and glutathione levels. Mechanistically, LYC enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by increased Nrf2 nuclear translocation and activity, along with the elevated phospho-Nrf2 expression. However, ML385, an inhibitor of Nrf2, effectively counteracted the antiferroptotic effects of LYC. Molecular docking studies, molecular dynamics simulations, and cellular thermal shift assays collectively demonstrated that LYC exhibited robust binding affinity with AMP-activated protein kinase (AMPK). Pretreatment with LYC activated AMPK signaling. However, inhibition of AMPK by Compound C diminished the effects of LYC on the AMPK/Nrf2 signaling pathway both in vitro and in vivo. Moreover, the function, morphology, and ferroptosis hallmarks of the livers were improved after LYC administration, while these parameters were reversed followi...