Mitochondrial SLC25A46 Rewires Fatty Acid Oxidation to Promote Cell Proliferation and Ferroptosis Evasion in Ovarian Cancer by Stabilizing CACT

ABSTRACT SLC25A46 is a mitochondrial intermembrane bridging protein reported to play a crucial role in mitochondrial network maintenance, yet its functional roles in human cancer metabolic rewiring and disease progression remain unexplored, including ovarian cancer (OC). Here, we revealed that SLC25A46 is markedly upregulated in OC and associated with poor patient outcomes. Functionally, SLC25A46 promoted OC growth by facilitating cell proliferation and ferroptosis evasion. Mechanistically, SLC25A46 promotes cell proliferation and ferroptosis evasion of OC cells by activating fatty acid oxidation‐mediated ATP and NADPH production via protecting carnitine‐acylcarnitine translocase (CACT) from MARCHF5‐mediated ubiquitin‐degradation. Notably, knockdown of SLC25A46 significantly increased the sensitivity of OC cells to ferroptosis and enhanced their cytotoxic response to carboplatin. Additionally, we found that PBX1 directly binds and transactivates the SLC25A46 promoter. Overall, our results highlight the critical role of SLC25A46/MARCHF5/CACT axis in facilitating cell proliferation and ferroptosis evasion in OC cells via activating fatty acid oxidation‐mediated ATP and NADPH production. These findings suggest that targeting SLC25A46 represents a rational strategy to improve treatment outcomes in OC patients.