SESN2 suppresses ferroptosis in polycystic ovary syndrome by maintaining PRDX6 K209 lactylation

Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous endocrine-metabolic disorder affecting women of reproductive age, characterized by elevated androgen levels, disrupted ovulation, and polycystic ovarian changes. Increasing evidence indicates that oxidative stress and ferroptosis contribute to granulosa cell dysfunction and ovarian impairment in PCOS. In this study, we identified sestrin 2 (SESN2), a stress-inducible metabolic regulator, as a protective factor against ferroptosis in PCOS. Using both in vitro and in vivo PCOS models, we demonstrate that SESN2 deficiency aggravates oxidative stress and ferroptosis in ovarian granulosa cells. Mechanistically, loss of SESN2 reduced the overall lactylation level of peroxiredoxin 6 (PRDX6) and was associated with decreased lactylation at the K209 site, a modification important for PRDX6-mediated redox homeostasis. Quantitative co-immunoprecipitation showed that PRDX6 interacted with GPX4, and this interaction was markedly weakened by K209R mutation. Consistently, re-expression of wild-type PRDX6, but not the K209R mutant, substantially attenuated SESN2 deficiency-induced oxidative stress and ferroptotic injury. Overall, these findings indicate that SESN2 suppresses ferroptosis in PCOS at least partly by maintaining PRDX6 K209 lactylation, highlighting the SESN2-PRDX6 pathway as a potential therapeutic target for PCOS.