WTAP -mediated N6‑methylation of TRAF6 Facilitates Polycystic Ovary Syndrome by Inducing Ferroptosis.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting 5-11% of reproductive-age women worldwide, yet its pathogenesis remains uncertain. Members of the tumor necrosis factor receptor-associated factor (TRAF) family are key regulators of immunity and inflammation, making them potential candidates in PCOS development. The present study investigated the role of TRAF6 in PCOS pathogenesis. TRAF6 was markedly upregulated in ovarian tissues of PCOS mice compared to other TRAF family members. TRAF6 overexpression repressed proliferation, induced apoptosis, enhanced oxidative stress, and facilitated ferroptosis in KGN cells. Bioinformatic prediction identified multiple m6A methylation sites on TRAF6. Consistently, both total m6A methylation levels and TRAF6 N6-methyladenosine (m6A) levels in ovarian tissues of PCOS mice were enhanced, accompanied by upregulated WTAP and METTL3. In KGN cells, WTAP overexpression, but not METTL3 overexpression, elevated TRAF6 N6-methyladenosine (m6A) levels. Furthermore, WTAP overexpression repressed proliferation, induced oxidative stress, and triggered ferroptosis in KGN cells, effects that were reversed by TRAF6 knockdown. Collectively, our findings indicate that WTAP-mediated N6-methyladenosine (m6A) of TRAF6 promotes oxidative stress and ferroptosis in granulosa cells (GCs), highlighting this axis as a potential target for PCOS treatment.