{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:04:26Z","timestamp":1789383866917,"version":"build-2803163510"},"reference-count":64,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Ovarian cancer (OV) is a highly lethal gynecological tumor, often developing platinum chemotherapy resistance and treatment failure. With their diverse and complex structures, natural products offer potential solutions to drug resistance. This study systematically examines chaetocin's effects on cisplatin\u2010resistant OV cells and its underlying molecular mechanisms. We utilized a cell counting Kit\u20108, transwell assays, flow cytometry, immunohistochemistry, and western blotting to evaluate chaetocin's effects on cisplatin\u2010resistant OV cells. Proteomic analysis and bioinformatics were utilized to identify the molecular targets of chaetocin, which were validated via cell transfection and co\u2010immunoprecipitation. Additionally, a cisplatin\u2010resistant OV xenograft model was developed for in\u00a0vivo studies. Chaetocin suppressed the malignancy of cisplatin\u2010resistant OV cells in a dose\u2010dependent manner to suppress cell proliferation, impede cell migration and invasion, and induce both cell apoptosis and cell cycle arrest. Furthermore, in\u00a0vivo studies showed that chaetocin inhibited tumor growth in a cisplatin\u2010resistant OV xenograft model. In terms of mechanism, chaetocin induced ferroptosis in these cells, inhibiting TFRC ubiquitination and upregulating its expression by reducing the levels of cullin1 and its neddylation binding (cullin1\u2010NEDD8). Our study uncovers a previously unrecognized mechanism: Chaetocin induces ferroptosis by inhibiting TFRC neddylation to upregulate its expression in OV. Unlike its known role as an SUV39H1 inhibitor, chaetocin functions through the neddylation\u2010TFRC\u2010ferroptosis axis, a pathway not previously linked to this compound. Moreover, while neddylation has recently been reported to regulate ferroptosis via SLC7A11, our study reveals an entirely distinct mechanism involving TFRC\u2010mediated iron transport. This epigenetic regulation stabilizes TFRC, sensitizing resistant cells to ferroptosis, providing a dual\u2010mechanistic insight not found in existing literature. By linking chaetocin's gene regulation to iron\u2010dependent cell death, we offer new insights and potential therapies for cisplatin\u2010resistant OV.<\/jats:p>","DOI":"10.1002\/ptr.70446","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:18:33Z","timestamp":1789381113000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chaetocin Induces Ferroptosis in Cisplatin\u2010Resistant Ovarian Cancer Cells Through Neddylation\u2010Mediated\n                    <scp>TFRC<\/scp>\n                    Upregulation"],"prefix":"10.1002","author":[{"given":"Hanfei","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Gynecologic Oncology Zhejiang Cancer Hospital  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wumin","family":"Dai","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Institute  Hangzhou Zhejiang 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