Lycopene alleviates zearalenone-induced endometrial ferroptosis in early pregnant sows by activating the Nrf2/GPX4 pathway.

Zearalenone (ZEA), a feed-borne mycotoxin, induces oxidative stress and triggers ferroptosis-related injury. Lycopene (LYC), a natural antioxidant carotenoid, has not been well characterized for its protective role against ZEA-induced uterine damage in pregnant sows. This study investigated the protective efficacy as well as the underlying molecular mechanisms of LYC against ZEA-induced uterine injury. Thirty-two pregnant sows were randomly assigned to groups and fed basal diets supplemented with ZEA (1 mg/kg) and/or LYC (400 mg/kg) on gestational days 1-35. Porcine endometrial epithelial cells were also exposed to ZEA and/or LYC at 25 μM. The results showed that LYC alleviated ZEA-induced uterine histopathological changes and hormone disorders, increased the number of implanted embryos and uterine organ index, enhanced glutathione peroxidase and superoxide dismutase activities together with total antioxidant capacity levels, and reduced malondialdehyde content, thereby mitigating oxidative stress in the endometrium. LYC also regulated the inflammatory response by lowering pro-inflammatory cytokines (IL-1β, IL-2, TNF-α), while enhancing anti-inflammatory cytokines (IL-4, IL-6, IL-10). Proteomic and untargeted metabolomic analyses revealed that ZEA-induced uterine damage was closely correlated with oxidative stress and ferroptosis. Mechanistically, LYC suppressed ferroptosis by activating the Nrf2/GPX4 pathway, upregulating the mRNA expression of GCLM, GPX4, and CP, and downregulating the protein levels of DMT1 and ACSL4. Collectively, LYC shows potential as a preventive or therapeutic strategy for ZEA-induced uterine damage.