Multiple mycotoxins contamination in foods and feeds threatens human and animal health after they accumulate in the food chain, producing various toxic effects. The common mycotoxins contaimination in feeds are zearalenone (ZEN), deoxynivalenol (DON), and aflatoxin B1 (AFB1), but the effects of their co-exposure on the jejunum are not well understood. Lycopene (LYC) has been reported to have antioxidant activity that alleviates jejunal damage. In this study, we investigated the possible role of LYC as a treatment to mitigate the combined effects of ZEN, DON, and AFB1 on the jejunum of mice. Eighty male specific-pathogen-free ICR mice were randomly allocated to treatments with LYC (10 mg kg^-1) and/or ZEN + DON + AFB1 (10 mg kg^-1 ZEN, 1 mg kg^-1 DON, and 0.5 mg kg^-1 AFB1). The results indicated that LYC alleviated ZEN + DON + AFB1-induced jejunal injury by ameliorating the jejunal structural injury and increasing the villus height/crypt depth ratio and the levels of tight junction proteins (zonula occludens 1 [ZO1], occludin1 and claudin1) in the mouse jejunum. LYC also inhibited the oxidative stress induced by co-exposure to ZEN, DON, and AFB1 via reducing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and enhancing the total antioxidant capacity (T-AOC). LYC also alleviated jejunal mitochondrial damage in the ZEN + DON + AFB1-affected mice, evident as an increase in mitochondrial fission 1 (Fis1) transcription and a reduction in mitochondrial mitofusin 1 (Mfn1) and Mfn2 transcription. Co-exposure to ZEN, DON, and AFB1 also significantly increased the transcription of ferroptosis-related genes (transferrin receptor 1 (Tfr1), ferritin heavy chain 1 [Fth1], solute carrier family 3 member 2 [Slc3a2], and glutathione peroxidase 4 [Gpx4]), TFR1 and Fe²⁺ concentration. Notably, LYC potentially alleviated ZEN + DON + AFB1-induced jejunal ferroptosis. These results demonstrate that LYC alleviates ZEN + DON + AFB1-induced jejunal toxicity by inhibiting oxidative stress-mediated ferroptosis and mitochondrial damage in mice.

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