Abstract
Ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for cancer treatment, particularly in hepatocellular carcinoma (HCC). However, the mechanisms underlying the regulation of ferroptosis in HCC remain to be unclear. In this study, we have identified a novel regulatory pathway of ferroptosis involving the inhibition of Apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme with dual functions in DNA repair and redox regulation. Our findings demonstrate that inhibition of APE1 leads to the accumulation of lipid peroxidation and enhances ferroptosis in HCC. At the molecular level, the inhibition of APE1 enhances ferroptosis which relies on the redox activity of APE1 through the regulation of the NRF2/SLC7A11/GPX4 axis. We have identified that both genetic and chemical inhibition of APE1 increases AKT oxidation, resulting in an impairment of AKT phosphorylation and activation, which leads to the dephosphorylation and activation of GSK3β, facilitating the subsequent ubiquitin-proteasome-dependent degradation of NRF2. Consequently, the downregulation of NRF2 suppresses SLC7A11 and GPX4 expression, triggering ferroptosis in HCC cells and providing a potential therapeutic approach for ferroptosis-based therapy in HCC. Overall, our study uncovers a novel role and mechanism of APE1 in the regulation of ferroptosis and highlights the potential of targeting APE1 as a promising therapeutic strategy for HCC and other cancers.
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This work was supported by the National Natural Science Foundation of China (32171407 and 82373183) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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Y.D., Y.Z., and X.Y. performed study concept and design; Z.H., Y.D., Z.G., L.H. and F.P. performed development of methodology and writing, review and revision of the paper; Y.D., Y.Z., X.Y., Z.H. and Z.G. provided acquisition, analysis and interpretation of data, and statistical analysis; F.P., Z.H., L.H. and Z.G. provided technical and material support. All authors read and approved the final paper.
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This research was approved by the Ethics Committee of Nanjing Normal University. All animal experiments were performed according to procedures approved by the Laboratory Animal Care Committee at Nanjing Normal University, in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
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Du, Y., Zhou, Y., Yan, X. et al. APE1 inhibition enhances ferroptotic cell death and contributes to hepatocellular carcinoma therapy. Cell Death Differ 31, 431–446 (2024). https://doi.org/10.1038/s41418-024-01270-0
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DOI: https://doi.org/10.1038/s41418-024-01270-0
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