This study investigates the role of ovarian ferroptosis in the development of polycystic ovary syndrome (PCOS). Ferroptosis, a recently discovered iron-dependent form of programmed cell death, was found to be increased in the ovaries of PCOS patients and rats with dehydroepiandrosterone (DHEA)-induced PCOS. The study used human granulosa cells (hGCs) from PCOS and non-PCOS patients, as well as a DHEA-induced PCOS rat model, to evaluate ferroptosis levels. Key findings include: 1. **Elevated Ferroptosis in PCOS Ovaries**: - Increased intracellular Fe2+ and malondialdehyde (MDA) concentrations were observed in hGCs from PCOS patients and ovaries from DHEA-induced PCOS rats. - Abnormal mitochondrial morphology and reduced cell viability were also noted in these samples. 2. **Ferroptosis Inhibition with Ferrostatin-1 (Fer-1)**: - Fer-1 treatment significantly reduced ferroptosis in the PCOS rat model, improving ovarian morphology, insulin resistance, estrous cycle disruption, and hyperandrogenism. - Fer-1 also improved oocyte quality and follicular development in PCOS rats. 3. **Mechanisms of Ferroptosis in PCOS**: - Dihydrotestosterone (DHT) induced ferroptosis in hGCs through NCOA4-dependent ferritinophagy, leading to decreased ferritin heavy chain 1 (FTH1) and increased glutathione peroxidase 4 (GPX4) levels. - Ferroptosis activator RSL3 induced PCOS-like traits, including polycystic ovaries, hyperandrogenism, and increased LH/FSH ratio. 4. **Discussion**: - The study provides direct evidence of excessive ferroptosis in PCOS ovaries, suggesting that ferroptosis inhibitors could be a potential therapeutic target for PCOS. - The findings highlight a potential 'vicious cycle' between hyperandrogenism and ferroptosis, which exacerbates PCOS symptoms. Overall, the study demonstrates that ovarian ferroptosis plays a crucial role in the pathogenesis of PCOS and suggests that targeting ferroptosis could be a promising approach for treating this condition.This study investigates the role of ovarian ferroptosis in the development of polycystic ovary syndrome (PCOS). Ferroptosis, a recently discovered iron-dependent form of programmed cell death, was found to be increased in the ovaries of PCOS patients and rats with dehydroepiandrosterone (DHEA)-induced PCOS. The study used human granulosa cells (hGCs) from PCOS and non-PCOS patients, as well as a DHEA-induced PCOS rat model, to evaluate ferroptosis levels. Key findings include: 1. **Elevated Ferroptosis in PCOS Ovaries**: - Increased intracellular Fe2+ and malondialdehyde (MDA) concentrations were observed in hGCs from PCOS patients and ovaries from DHEA-induced PCOS rats. - Abnormal mitochondrial morphology and reduced cell viability were also noted in these samples. 2. **Ferroptosis Inhibition with Ferrostatin-1 (Fer-1)**: - Fer-1 treatment significantly reduced ferroptosis in the PCOS rat model, improving ovarian morphology, insulin resistance, estrous cycle disruption, and hyperandrogenism. - Fer-1 also improved oocyte quality and follicular development in PCOS rats. 3. **Mechanisms of Ferroptosis in PCOS**: - Dihydrotestosterone (DHT) induced ferroptosis in hGCs through NCOA4-dependent ferritinophagy, leading to decreased ferritin heavy chain 1 (FTH1) and increased glutathione peroxidase 4 (GPX4) levels. - Ferroptosis activator RSL3 induced PCOS-like traits, including polycystic ovaries, hyperandrogenism, and increased LH/FSH ratio. 4. **Discussion**: - The study provides direct evidence of excessive ferroptosis in PCOS ovaries, suggesting that ferroptosis inhibitors could be a potential therapeutic target for PCOS. - The findings highlight a potential 'vicious cycle' between hyperandrogenism and ferroptosis, which exacerbates PCOS symptoms. Overall, the study demonstrates that ovarian ferroptosis plays a crucial role in the pathogenesis of PCOS and suggests that targeting ferroptosis could be a promising approach for treating this condition.