Abstract
Reprogramming of lipid metabolism is a hallmark of malignant tumors, and targeting key enzymes in lipid metabolism has emerged as a critical strategy to inhibit tumor progression. Sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipid biosynthesis, drives lipid metabolic reprogramming that not only promotes malignant progression but also confers resistance to ferroptosis in tumor cells. Ferroptosis is a distinct form of regulated cell death characterized by iron accumulation and lipid peroxidation. In this study, we demonstrate that silencing SREBP1 in ovarian cancer cells leads to decreased glutathione (GSH) levels, reduced protein expression of XCT and GPX4, and increased levels of malondialdehyde (MDA) and lipid peroxidation, indicating that SREBP1 silencing induces ferroptosis in ovarian cancer cells. Further experiments, including the CCK-8, EdU, colony formation assays and flow cytometry, confirmed that SREBP1 silencing suppresses proliferation by inducing cell cycle arrest. Transwell assays, immunofluorescence (IF) staining, Nile Rad staining, and measurements of triglyceride (TG) and total cholesterol (TC) levels demonstrated that SREBP1 silencing inhibits epithelial–mesenchymal transition (EMT) and lipid synthesis in ovarian cancer cells. Notably, SREBP1 silencing downregulates the expression of Nrf2, and treatment with the Nrf2 activator THBQ reverses the effects of SREBP1 silencing on ovarian cancer cell proliferation and ferroptosis. Mechanistically, SREBP1 silencing promotes ubiquitination-mediated degradation of the Nrf2 protein, thereby suppressing the expression of XCT and GPX4, ultimately triggering ferroptosis in ovarian cancer cells. Our findings establish SREBP1 as a key mediator of ferroptosis resistance and nominates it as both a therapeutic target and a potential prognostic biomarker in ovarian cancer.
Schematic diagram illustrating the mechanism whereby silent SREBP1 mediates the Nrf2/XCT/GPX4 pathway to induce ferroptosis in ovarian cancer cells.
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All data supporting the findings of this study are included in the article and its supplementary information files.
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This research was supported by the Projects of Science and Technology Department of Jilin Province (No.202002021JC) and The National Natural Science Foundation of China (No.82360576).
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Rui Nie and Hou-kun Zhou were involved in the conception and design of the study; Rui Nie and Hai-yan Quan performed in vitro experiments and drafting of the manuscript; Lin Chen and Yuan Zhang performed in vivo experiments and data analysis；Rui Nie, Hou-kun Zhou, and Zhen-hua Lin were manuscript revisions. All authors listed approved the final version of the manuscript.
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The Shanghai Outdo Biotech Co., Ltd.’s Institutional Review Board (IRB) examined and approved the research procedure. The IRB approval number for this study is SHYJS-CP-1804011 and SHYJS-CP-1804032. Animal experiments were approved by Yanbian University’s Ethics Committee (Approval No. YD20250710017) and conducted in strict accordance with institutional and national guidelines for the care and use of laboratory animals. All methods are compliant with the ARRIVE guidelines.
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Nie, R., Zhou, H., Chen, L. et al. SREBP1 knockdown triggers ferroptosis by suppressing the Nrf2-XCT/GPX4 axis in ovarian cancer. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02964-9
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DOI: https://doi.org/10.1038/s41420-026-02964-9
