Zearalenone causes female reproductive lipotoxicity through the ERα-CD36/TLR4 signaling pathway

Exposure to zearalenone (ZEN), an estrogen-like mycotoxin produced by Fusarium fungi, impairs reproductive performance and farm-animal welfare; however, the underlying mechanism remains unclear. Using female pigs as the large animal model, we demonstrate that ZEN-induced reproductive lipotoxicity is associated with alterations in estrogen receptor-alpha (ERα) expression, diacylglycerol levels, and pro-inflammatory cytokine production. Mechanistically, upregulated ERα directly binds to the promoter regions of Cd36 and Tlr4 in the nucleus, leading to increased expression of the lipid transporter CD36 and the inflammatory receptor TLR4, as well as enhanced CD36-TLR4 interaction. This subsequently results in diacylglycerol accumulation and inflammation. Consistently, studies using Cd36-knockout mice and the TLR4-specific inhibitor TAK-242 reveal that ZEN-induced reproductive lipotoxicity is dependent on the ERα-CD36/TLR4 axis. Furthermore, dietary supplementation with the ZEN-degrading enzyme ZLHY-6 in female pigs also counteracts ZEN-induced reproductive lipotoxicity through the inhibition of the ERα-CD36/TLR4 signaling pathway. Together, these findings reveal a novel mechanism underlying ZEN-induced reproductive lipotoxicity, and highlight the ERα-CD36/TLR4 axis as a potential therapeutic target.