Chaetocin Induces Ferroptosis in Cisplatin‐Resistant Ovarian Cancer Cells Through Neddylation‐Mediated TFRC Upregulation

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-resistant OV cells and its underlying molecular mechanisms. We utilized a cell counting Kit-8, transwell assays, flow cytometry, immunohistochemistry, and western blotting to evaluate chaetocin's effects on cisplatin-resistant OV cells. Proteomic analysis and bioinformatics were utilized to identify the molecular targets of chaetocin, which were validated via cell transfection and co-immunoprecipitation. Additionally, a cisplatin-resistant OV xenograft model was developed for in vivo studies. Chaetocin suppressed the malignancy of cisplatin-resistant OV cells in a dose-dependent manner to suppress cell proliferation, impede cell migration and invasion, and induce both cell apoptosis and cell cycle arrest. Furthermore, in vivo studies showed that chaetocin inhibited tumor growth in a cisplatin-resistant 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-NEDD8). 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-TFRC-ferroptosis 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-mediated iron transport. This epigenetic regulation stabilizes TFRC, sensitizing resistant cells to ferroptosis, providing a dual-mechanistic insight not found in existing literature. By linking chaetocin's gene regulation to iron-dependent cell death, we offer new insights and potential therapies for cisplatin-resistant OV.