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Here, we demonstrate that oral exposure to BPF (as low as 250 \u03bcg\/kg) induces ovarian hypertrophy, disrupted follicular architecture and cumulus-oocyte communication, and reduced serum estradiol and progesterone in mice by triggering ferroptosis. Integrating multiomics approaches, we identified NCOA4-mediated ferritinophagy as the central cellular driver of this process. In granulosa cells, pharmacologic inhibition of autophagy and gene silencing blocked NCOA4 phosphorylation, ferritin degradation, iron overload, and ferroptosis. Mechanistically, we reveal a new signaling axis wherein BPF promotes the physical interaction between membrane-associated ER\u03b2 and the kinase ATM. This interaction triggers ATM activation and subsequent phosphorylation of NCOA4, thereby accelerating ferritin degradation and iron overload. Structural analysis identifies G2296 as the critical interface residue; importantly, an ATM\u2013G2296A point mutation disrupts the ER\u03b2\u2013ATM interaction and abolishes BPF-induced ferroptosis. These findings elucidate a distinct molecular mechanism of ovarian injury driven by low-dose BPF exposure, underscoring the urgent need to reassess the safety profiles of BPF-containing materials.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c08276","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:02:20Z","timestamp":1785902540000},"page":"25674-25689","source":"Crossref","is-referenced-by-count":0,"title":["Bisphenol F Exposure\nInduces Ovarian Ferroptosis via\nthe ER\u03b2\u2013ATM\u2013Ferritinophagy Axis"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2479-3047","authenticated-orcid":true,"given":"Guangyu","family":"Liu","sequence":"first","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lv","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jueshun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolin","family":"Mo","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhu","family":"Ma","sequence":"additional","affiliation":[{"name":"China Agricultural University , , ,","place":["Beijing, China, 100080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruziev Khurshed","family":"Tuychievich","sequence":"additional","affiliation":[{"name":"Tajik Agrarian University Named After Shirinshoh Shohtemur , , ,","place":["Dushanbe, Tajikistan, 734002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Il","family":"Yelena","sequence":"additional","affiliation":[{"name":"M.Kozybayev North Kazakhstan University , , ,","place":["Petropavlovsk, Kazakhstan, 150000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7822-4520","authenticated-orcid":true,"given":"Zhongliang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"10","key":"2026081910175808600_cit1","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/s41574-025-01131-x","article-title":"Endocrine-Disrupting Chemicals and Female Reproductive\nHealth: A Growing Concern","volume":"21","author":"Parent","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"issue":"2","key":"2026081910175808600_cit2","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2022.158258","article-title":"Mechanism of Action and Neurotoxic\nEffects of Chronic Exposure to Bisphenol F in Adult Zebrafish","volume":"851","author":"Kim","year":"2022","journal-title":"Sci. Total Environ."},{"issue":"20","key":"2026081910175808600_cit3","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202412177","article-title":"Injectable Hydrogel Loaded with Plasma-Rich Platelets\nRepairing Endometrial Injury and Remodeling Reproductive Function\nby Regulating PI3K\/AKT Pathway","volume":"21","author":"Zhang","year":"2025","journal-title":"Small"},{"issue":"1","key":"2026081910175808600_cit4","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-81231-6","article-title":"Bisphenol A, S or F Mother\u2019s Dermal Impregnation\nImpairs Offspring Immune Responses in a Dose and Sex-Specific Manner\nin Mice","volume":"11","author":"Malaise\u0301","year":"2021","journal-title":"Sci. Rep."},{"issue":"7","key":"2026081910175808600_cit5","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1289\/ehp.1408989","article-title":"Bisphenol S and\nF: A Systematic Review and Comparison\nof the Hormonal Activity of Bisphenol A Substitutes","volume":"123","author":"Rochester","year":"2015","journal-title":"Environ. Health Perspect."},{"key":"2026081910175808600_cit6","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.envpol.2017.03.018","article-title":"Fate and\nMass Balance of Bisphenol Analogues in Wastewater\nTreatment Plants in Xiamen City, China","volume":"225","author":"Sun","year":"2017","journal-title":"Environ.\nPollut."},{"key":"2026081910175808600_cit7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2020.111481","article-title":"Occurrence, Toxicity\nand Ecological Risk of Bisphenol A Analogues\nin Aquatic Environment\u2013A Review","volume":"208","author":"Liu","year":"2021","journal-title":"Ecotoxicol.\nEnviron. Saf."},{"key":"2026081910175808600_cit8","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.ecoenv.2019.04.083","article-title":"Occurrence,\nDistribution, Bioaccumulation, and Ecological Risk of Bisphenol Analogues,\nParabens and Their Metabolites in the Pearl River Estuary, South China","volume":"180","author":"Zhao","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"2026081910175808600_cit9","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2022.107530","article-title":"Use of High-Resolution\nMetabolomics to Assess the Biological Perturbations\nAssociated with Maternal Exposure to Bisphenol A and Bisphenol F among\nPregnant African American Women","volume":"169","author":"Tchen","year":"2022","journal-title":"Environ. Int."},{"key":"2026081910175808600_cit10","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2024.118433","article-title":"Urinary Concentrations\nof Bisphenol A and Its Alternatives:\nPotential Predictors of and Associations with Antral Follicle Count\namong Women from an Infertility Clinic in Northern China","volume":"249","author":"Zhang","year":"2024","journal-title":"Environ. Res."},{"key":"2026081910175808600_cit11","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2023.121393","article-title":"FTO-Nrf2 Axis\nRegulates Bisphenol F-Induced Leydig\nCell Toxicity in an m6A-YTHDF2-Dependent Manner","volume":"325","author":"Zhou","year":"2023","journal-title":"Environ. Pollut."},{"issue":"1","key":"2026081910175808600_cit12","doi-asserted-by":"publisher","DOI":"10.1186\/s12199-019-0797-5","article-title":"Effect of Bisphenol F, an Analog\nof Bisphenol A, on the Reproductive\nFunctions of Male Rats","volume":"24","author":"Ullah","year":"2019","journal-title":"Environ. Health Prev.\nMed."},{"issue":"5","key":"2026081910175808600_cit13","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis:\nAn Iron-Dependent Form of Nonapoptotic Cell Death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"issue":"14","key":"2026081910175808600_cit14","doi-asserted-by":"publisher","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis\nTurns 10: Emerging Mechanisms, Physiological Functions, and Therapeutic\nApplications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"issue":"2","key":"2026081910175808600_cit15","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis:\nA Regulated\nCell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"issue":"1","key":"2026081910175808600_cit16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1530\/REP-18-0058","article-title":"Initiation\nof Follicular Atresia: Gene Networks during Early Atresia in Pig Ovaries","volume":"156","author":"Zhang","year":"2018","journal-title":"Reproduction"},{"key":"2026081910175808600_cit17","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115415","article-title":"The Emerging\nRole of Ferroptosis in Female Reproductive\nDisorders","volume":"166","author":"Liu","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"2026081910175808600_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2024.124531","article-title":"FTO Mediates Bisphenol\nF-Induced Blood-Testis Barrier Impairment through Regulating Ferroptosis\nvia YTHDF1\/TfRc and YTHDF2\/SLC7A11 Signal Axis","volume":"359","author":"Shi","year":"2024","journal-title":"Environ. Pollut."},{"issue":"1","key":"2026081910175808600_cit19","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s12403-022-00483-3","article-title":"Occurrence and Exposure\nAssessment\nof Bisphenol Analogues Through Different Types of Drinking Water in\nKorea","volume":"15","author":"Lim","year":"2023","journal-title":"Exposure Health"},{"issue":"6","key":"2026081910175808600_cit20","doi-asserted-by":"publisher","first-page":"6523","DOI":"10.1021\/acsomega.8b00824","article-title":"Exposure to Bisphenol A, Bisphenol\nF, and Bisphenol S in U.S. Adults and Children: The National Health\nand Nutrition Examination Survey 2013\u20132014","volume":"3","author":"Lehmler","year":"2018","journal-title":"ACS Omega"},{"issue":"1","key":"2026081910175808600_cit21","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s12403-024-00654-4","article-title":"Urinary Concentrations\nof BPA and Analogous Bisphenols (BPF and BPS) among School Children\nfrom Poland: Exposure and Risk Assessment in the REPRO_PL Cohort","volume":"17","author":"Gari\u0301","year":"2025","journal-title":"Exposure Health"},{"key":"2026081910175808600_cit22","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2024.124800","article-title":"The Toxic Effects and\nMechanisms of Maternal Exposure to Bisphenol F during Gestation and\nLactation on Lungs in Female Offspring Mice","volume":"361","author":"Du","year":"2024","journal-title":"Environ. Pollut."},{"key":"2026081910175808600_cit23","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2024.125546","article-title":"Effect of Bisphenol F on Reproductive\nFunction in F1 Generation Male\nMice and Its Potential Mechanisms","volume":"367","author":"Li","year":"2025","journal-title":"Environ.\nPollut."},{"key":"2026081910175808600_cit24","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2023.107770","article-title":"Transient Developmental Exposure\nto Low Doses of Bisphenol F Negatively Affects Neurogliogenesis and\nOlfactory Behaviour in Adult Mice","volume":"172","author":"Vancamp","year":"2023","journal-title":"Environ.\nInt."},{"issue":"18","key":"2026081910175808600_cit25","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241814129","article-title":"Activation of NLRP3\nInflammasome in Liver of Long Evans Lactating Rats and Its Perinatal\nEffects in the Offspring after Bisphenol F Exposure","volume":"24","author":"Linillos-Pradillo","year":"2023","journal-title":"Int. J. Mol. Sci."},{"issue":"6","key":"2026081910175808600_cit26","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1007\/s00204-022-03246-w","article-title":"Pharmacokinetics\nand Toxicity Evaluation Following Oral Exposure to Bisphenol F","volume":"96","author":"Lee","year":"2022","journal-title":"Arch. Toxicol."},{"key":"2026081910175808600_cit27","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi0814s24","article-title":"Using AutoDock\nfor Ligand-Receptor\nDocking","volume":"24","author":"Morris","year":"2008","journal-title":"Curr. Protoc Bioinform."},{"issue":"6","key":"2026081910175808600_cit28","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1073\/pnas.89.6.2195","article-title":"Molecular Surface Recognition: Determination of Geometric\nFit between Proteins and Their Ligands by Correlation Techniques","volume":"89","author":"Katchalski-Katzir","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"1","key":"2026081910175808600_cit29","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/9.1.37","article-title":"Long-Distance\nPotentials: An Approach to the Multiple-Minima Problem in Ligand-Receptor\nInteraction","volume":"9","author":"Vakser","year":"1996","journal-title":"Protein Eng."},{"issue":"6","key":"2026081910175808600_cit30","doi-asserted-by":"publisher","first-page":"3244","DOI":"10.1093\/nar\/gkaa003","article-title":"rRNA Expansion Segment\n27Lb Modulates the Factor Recruitment\nCapacity of the Yeast Ribosome and Shapes the Proteome","volume":"48","author":"Shankar","year":"2020","journal-title":"Nucleic Acids Res."},{"issue":"6","key":"2026081910175808600_cit31","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1074\/mcp.TIR119.001646","article-title":"DEqMS: A Method\nfor Accurate Variance Estimation in Differential Protein Expression\nAnalysis","volume":"19","author":"Zhu","year":"2020","journal-title":"Mol. Cell. 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Cancer Res."},{"key":"2026081910175808600_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2024.153847","article-title":"Analysis of\nEnvironmental Pollutant Bisphenol F Elicited Prostate Injury Targets\nand Underlying Mechanisms through Network Toxicology, Molecular Docking,\nand Multi-Level Bioinformatics Data Integration","volume":"506","author":"Huang","year":"2024","journal-title":"Toxicology"},{"issue":"6","key":"2026081910175808600_cit42","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1007\/s00204-019-02442-5","article-title":"Naturally Occurring Bisphenol F in Plants Used in Traditional\nMedicine","volume":"93","author":"Huang","year":"2019","journal-title":"Arch. 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Res."},{"issue":"6","key":"2026081910175808600_cit46","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1002\/tox.23494","article-title":"Bisphenol F Exposure\nAffects Mouse\nOocyte in Vitro Maturation through Inducing Oxidative Stress and DNA\nDamage","volume":"37","author":"Ding","year":"2022","journal-title":"Environ. Toxicol."},{"key":"2026081910175808600_cit47","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2021.115409","article-title":"Exposure to\nAlternative Bisphenols BPS and BPF through Breast Milk: Noxious Heritage\nEffect during Nursing Associated with Idiopathic Infertility","volume":"413","author":"Nevoral","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2026081910175808600_cit48","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2026.106105","article-title":"Oral Repeated Dose Toxicity Study\nof Bisphenol F in Rats","volume":"169","author":"Lee","year":"2026","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"2026081910175808600_cit49","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.freeradbiomed.2025.01.035","article-title":"Bisphenol F Induces Spermatogenic\nCell Ferroptosis via FTO-Mediated m6A Regulation of FTH1","volume":"229","author":"Zhou","year":"2025","journal-title":"Free Radical Biol. Med."},{"issue":"1","key":"2026081910175808600_cit50","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42313-8","article-title":"Estrogen\nReceptor Beta Enhances Chemotherapy Response\nof GBM Cells by down Regulating DNA Damage Response Pathways","volume":"9","author":"Zhou","year":"2019","journal-title":"Sci. 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