Mp05-05 Darolutamide Mediated Pufa/Mufa Ratio to Mediate Lipid Peroxidation Through Ar-Srebp1-Fasn Axis and Synergizeds With Ferroptosis Inducers in Prostate Cancer

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP05)1 May 2024MP05-05 DAROLUTAMIDE MEDIATED PUFA/MUFA RATIO TO MEDIATE LIPID PEROXIDATION THROUGH AR-SREBP1-FASN AXIS AND SYNERGIZEDS WITH FERROPTOSIS INDUCERS IN PROSTATE CANCER Li BingHeng and Hai Huang Li BingHengLi BingHeng and Hai HuangHai Huang View All Author Informationhttps://doi.org/10.1097/01.JU.0001008740.27639.cc.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is one of the most common cancers in men and remains the leading cause of death in worldwide. Recently, some reports showed that ADT or iron combined with ferroptosis inducers had better tumor suppression and higher lipid peroxidation, respectively. However, the relationship between darolutamide and ferroptosis is still unclear. METHODS: In this study, we utilized lipidomic, transcriptomic and functional analyses, we demonstrate that Darolutamide increased the ratio of PUFA/MUFA, remodeling oxidized phospholipids, such as PC. Futhermore, we domonstrated that the inhibition of AR-SREBP1-FASN axis promptes ferroptosis, characterized by the accumulation of lipid peroxidation. Finally, Our vivo and vitro experiments showed that Darolutamide combined with ferroptosis inducers had better anti-tumorigenesis. RESULTS: The GEO database found that ferroptosis and oxidative phosphorylation enrichment were enhanced after Darolutmiade treatment. Lipidomics and metabolomics results showed that Darolutamide treatment showed an increase in the proportion of polyunsaturated fatty acids and a decrease in the proportion of saturated fatty acids. In addition, lipids in the cell membrane are remodeled, with an increase in phosphatidylcholine and a decrease in phosphatidylethanolamine. Detection of lipid peroxidation indicators in vivo and in vitro showed that the levels of BODIPY C11 and MDA increased after Darolutmaide treatment. Sequencing analysis of cells treated with Darolutamide showed that the downstream AR-SREBP1-FASN axis is involved in mediating ferroptosis. Further research findings demonstrate that AR-SREBP1-FASN leads to an imbalance in the balance of saturated fatty acids and polyunsaturated fatty acids in the cell membrane through downstream reduction of palmitate, ultimately leading to ferroptosis. Exogenous supplementation of palmitate can effectively inhibit ferroptosis in vitro. In vivo experimental results show that Darolumide can synergistically inhibit tumors and promote ferroptosis with ferroptosis inducers. CONCLUSIONS: Darolutamide mediated PUFA/MUFA ratio to mediate lipid peroxidation through AR-SREBP1-FASN axis and synergizeds with ferroptosis inducers in prostate cancer.The specific mechanism is by inhibiting palmitate, a downstream product of the AR-SREBP1-FASN axis, leading to lipid imbalance in the cell membrane and an increase in the proportion of polyunsaturated fatty acids, ultimately inducing ferroptosis. Source of Funding: This work was supported by the National key R&D plan of China (2022YFC3602904); the National Natural Science Foundation of China (No:81974395, No:82173036) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e44 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Li BingHeng More articles by this author Hai Huang More articles by this author Expand All Advertisement PDF downloadLoading ...