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Although several studies suggest that cancer cells display characteristics of \u2018Iron addiction\u2019, an ongoing debate surrounds the question of whether iron can influence the malignant properties of ovarian cancer. In the current study, we initially found iron levels increase during spheroid formation. Furthermore, iron supplementation can promote cancer cell survival, cancer spheroid growth, and migration; vice versa, iron chelators inhibit this process. Notably, iron reduces the sensitivity of ovarian cancer cells to platinum as well. Mechanistically, iron downregulates DNA homologous recombination (HR) inhibitor polymerase theta (POLQ) and relieves its antagonism against the HR repair enzyme RAD51, thereby promoting DNA damage repair to resist chemotherapy-induced damage. Additionally, iron tightly regulated by ferritin (FTH1\/FTL) which is indispensable for iron-triggered DNA repair. Finally, we discovered that iron chelators combined with platinum exhibit a synergistic inhibitory effect on ovarian cancer in vitro and in vivo. Our findings affirm the pro-cancer role of iron in ovarian cancer and reveal that iron advances platinum resistance by promoting DNA damage repair through FTH1\/FTL\/POLQ\/RAD51 pathway. Our findings highlight the significance of iron depletion therapy, revealing a promising avenue for advancing ovarian cancer treatment.<\/jats:p>","DOI":"10.1038\/s41419-024-06688-5","type":"journal-article","created":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:02:52Z","timestamp":1715576572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1\/FTL\/POLQ\/RAD51 axis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5284-6257","authenticated-orcid":false,"given":"Qingyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weifeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunbo","family":"Di","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0775-9453","authenticated-orcid":false,"given":"Ning","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizhen","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,13]]},"reference":[{"key":"6688_CR1","first-page":"7","volume":"72","author":"RL Siegel","year":"2022","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. 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Informed consent was obtained from all participants or their legally authorized representatives. Before any data or sample collection, participants or their representatives were informed about the study\u2019s nature, purpose, risks, and benefits. Participants voluntarily consented to participate, understanding the voluntary nature of their involvement and that the study was performed in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"329"}}