Deoxynivalenol Impairs Ovarian Function by Triggering Ferroptosis in Granulosa Cells through <i>GPX2</i> Inhibition and Oxidative Stress

Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, is a widespread cereal contaminant that impairs swine growth and reproduction. Although DON-induced ovarian dysfunction has been reported, its underlying molecular mechanisms remain incompletely defined. We constructed DON exposure models in piglets and porcine ovarian granulosa cells to investigate conserved pathogenic mechanisms. Integrative transcriptomic and Cleavage Under Targets and Tagmentation (CUT&Tag) analyses identified GPX2 as a key target. DON inhibited glycolytic lactate production, reducing H3K18 lactylation at the GPX2 promoter and repressing transcription. GPX2 depletion disrupted redox homeostasis, induced oxidative stress and mitochondrial dysfunction, and triggered ferroptosis, impairing steroidogenesis. Ferrostatin-1 or GPX2 overexpression alleviated DON-induced injury and restored endocrine function. These pathogenic effects were conserved in DON-treated mice, confirming evolutionary conservation across mammals. Collectively, our findings reveal a metabolically and epigenetically regulated GPX2-glutathione-ferroptosis axis mediating DON ovarian toxicity, providing a potential therapeutic target for mitigating mycotoxin-related reproductive disorders.