PPARγ Is Critical for Lycopene Antagonizing Zearalenone-Induced Ferroptosis by Promoting Autophagy-Mediated TFRC Degradation in Swine Testicular Cells

Mycotoxins are common contaminants in agricultural products and feed, which pose a serious threat to public health. Zearalenone (ZEA) is a well-known environmental endocrine disruptor that causes reproductive disorders. Lycopene (LYC) is a possible therapeutic and preventive agent for male diseases. Here, we aim to explore the mechanism of ZEA-induced swine testicular (ST) cell injury and antagonism of lycopene. ST cells were treated with lycopene and/or ZEA for mechanistic validation. In this study, ZEA caused pronounced mitochondrial structural damage, whereas lycopene restored mitochondrial integrity. Lycopene also reduced ZEA-induced lipid peroxidation and ferrous ion levels, eventually inhibiting ferroptosis. Mechanistically, lycopene recovered PPARγ expression and regulated AMPK/mTOR signaling, thereby facilitating TFRC turnover. Of note, PPARγ knockdown weakened the effects of lycopene on ferroptosis, whereas TFRC overexpression diminished the protection afforded by autophagy activation. These findings indicate that lycopene mitigates ZEA-induced ferroptosis by regulating the PPARγ-AMPK-mTOR pathway and thus promoting autophagy-mediated TFRC degradation.