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As a natural aliphatic polyamine, spermidine exerts antioxidant activity and plays an anti-ferroptosis role in the pathogenesis of various diseases. However, the role and underlying mechanism of spermidine in iron overload-induced ovarian ferroptosis remain largely elusive. This study aimed to investigate the therapeutic potential of spermidine against iron overload-induced ferroptosis in ovarian granulosa cells and elucidate its molecular mechanism. As a result, iron overload models were established in female mice (in vivo, ferrous sulfate) and porcine ovarian granulosa cells (in vitro, ferric ammonium citrate), with spermidine administered at 3 mM (in vivo) or 150 \u03bcM (in vitro). Ferritin heavy chain (FHC) and solute carrier family 7 member 11 (SLC7A11) silencing were performed via siRNA transfection, and relevant controls were set. In vivo studies showed that spermidine elevated serum estradiol and progesterone levels, enhanced ovarian catalase (CAT) and superoxide dismutase (SOD) activities, improved granulosa cell mitochondrial morphology, and increased estrous cycle regularity from 35.6% (high-iron group) to 63.1%. In vitro, spermidine improved ferric ammonium citrate (FAC)-impaired cell viability; attenuated reactive oxygen species (ROS) accumulation; upregulated FHC, Nrf2\/p-Nrf2\/GPX4, SLC7A11 and anti-m\u00fcllerian hormone (AMH) expression; and inhibited excessive autophagy (decreased LC3BII\/I ratio). Mechanistically, spermidine activated AKT-mediated autophagy, modulated iron homeostasis and glutathione (GSH) synthesis via FHC, alleviated ferroptosis-related Nrf2\/p-Nrf2\/HO-1 pathway overactivation, reduced lipid peroxidation and DNA damage, and restored mitochondrial function. SLC7A11 silencing disrupted glutathione metabolism, induced mitochondrial ROS accumulation, and inhibited autophagy. Proteomic analysis identified microsomal glutathione S-transferase 3 (MGST3) as a potential key downstream target of spermidine in suppressing SLC7A11-mediated ferroptosis. This study reveals a novel therapeutic strategy wherein spermidine protects against ovarian ferroptosis and preserves ovarian function by regulating iron homeostasis through the FHC\/SLC7A11 axis.<\/jats:p>","DOI":"10.3390\/antiox15050637","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:02:27Z","timestamp":1779375747000},"page":"637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spermidine Targets Ovarian Granulosa Cells via Activating the FHC\/SLC7A11 Axis to Regulate Iron Homeostasis and Ameliorate Iron Overload-Induced Ovarian Dysfunction"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5457-753X","authenticated-orcid":false,"given":"Chun-Yang","family":"Niu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Department of Animal Science, College of Smart Animal Husbandry, College of Biology and Food, Shangqiu Normal University, Shangqiu 476000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-308X","authenticated-orcid":false,"given":"Dong-Mei","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0308-2588","authenticated-orcid":false,"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7727-4662","authenticated-orcid":false,"given":"Guan-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Animal Science, College of Smart Animal Husbandry, College of Biology and Food, Shangqiu Normal University, Shangqiu 476000, China"},{"name":"Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Ni","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Weng","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8993-2933","authenticated-orcid":false,"given":"Xiao-Guang","family":"An","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Kang","family":"Ling","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural 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