Deoxynivalenol induces ferroptosis via inhibiting glycolysis-H3K18la-STEAP3 axis to promote ovary damage in piglets.

Deoxynivalenol (DON), a prevalent mycotoxin in contaminated feed, compromises ovarian function through dual disruption of redox homeostasis and metabolic networks. However, the precise mechanisms underlying DON-induced toxicity and effective strategies to mitigate its reproductive consequences remain incompletely understood. This study reveals the molecular mechanism by which DON induces ferroptosis in porcine granulosa cells through the glycolysis-H3K18la-STEAP3 axis and elucidates how melatonin alleviates DON toxicity via metabolic reprogramming. Multi-omics analyses demonstrate that DON exposure disrupts glycolysis, reduces lactate, and diminished H3K18la. This process is also mediated by the downregulation of P300, a key writer of lactylation, which collectively suppress H3K18la. The loss of H3K18la decreased STEAP3 expression, intracellular iron accumulation, elevated lipid peroxidation, and downregulation of GPX4, ultimately triggering ferroptosis. Furthermore, melatonin restores H3K18la and STEAP3 expression both in vitro and vivo, thereby suppressing ferroptosis and reducing oxidative stress. These findings provide novel molecular targets and therapeutic strategies for DON intoxication.