P53-assisted METTL14-mediated m⁶A modification of SLC7A11 drives ferroptosis and inflammation in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is characterized by chronic inflammation and follicular arrest, yet the molecular drivers linking these pathologies to granulosa cell (GC) death remain elusive. Here, we identify a ferroptosis-inflammation cascade as a critical determinant of ovarian dysfunction in PCOS. We demonstrate that the N⁶-methyladenosine (m⁶A) methyltransferase METTL14 is aberrantly upregulated in human PCOS GCs, correlating with oxidative damage. Mechanistically, we uncover a non-canonical paradigm where upregulated P53 functions as an essential RNA-binding cofactor, recruiting METTL14 to the SLC7A11 transcript. Validated by AlphaFold3 modeling, this METTL14-p53 complex catalyzes SLC7A11 m⁶A hypermethylation and mRNA destabilization. The resulting SLC7A11 deficiency dismantles antioxidant defenses, driving ferroptosis and amplifying local inflammation. Crucially, in a DHEA-induced PCOS rat model, genetic ablation of Tp53 severed this pathogenic axis, restoring redox balance, suppressing inflammation, and reversing the polycystic phenotype. Collectively, our findings reveal a pivotal epigenetic mechanism linking m⁶A reprogramming, iron-dependent cell death, and inflammation, highlighting the METTL14-p53-SLC7A11 axis as a therapeutic target in PCOS.