SLC25A39 potentiates the RXFP1/cAMP/PKA/CREB axis to drive metabolic reprogramming and tumor progression in ovarian cancer

The mitochondrial transporter SLC25A39 mediates GSH transport from the cytosol to mitochondria and is essential for maintaining mitochondrial oxidative homeostasis and function. However, its exact molecular mechanism in ovarian cancer has not yet been elucidated. In the present work, protein and mRNA expression levels were measured using database analysis, IHC, IF, Western blot, and RT-qPCR. Cell proliferation, apoptosis, and migration capabilities were assessed by functional assays. Mitochondrial function was assessed by measuring glutathione reductase activity, ROS, MMP, and mPTP opening status. Energy metabolism was quantified through ATP content, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR). Transcriptomics, metabolomics and proteomics analyses combined with ChIP and experiments on gain and loss of function were carried out to explore associated signaling pathways, with final validation conducted in mouse models. The results show that SLC25A39 expression was upregulated in ovarian cancer tissues. Ovarian cancer cell proliferation and migration were markedly enhanced, while apoptosis was suppressed, upon SLC25A39 overexpression. Furthermore, SLC25A39 overexpression drove significant metabolic reprogramming, characterized by elevated GSH levels, reduced ROS production, increased MMP, closed mPTP, augmented ATP generation, and concurrently enhanced oxidative phosphorylation (OCR) and glycolytic flux (ECAR). Mechanistically, SLC25A39 potentiated the RXFP1/cAMP/PKA/CREB signaling axis by remodeling the intracellular redox and energy microenvironment, thereby driving metabolic reprogramming and promoting cell survival in ovarian cancer. Critically, CREB specifically bound to the SLC25A39 promoter, establishing a reciprocal reinforcing transcriptional regulatory circuit. These findings were further validated in vivo through animal experiments. In conclusion, SLC25A39 orchestrates metabolic reprogramming and promotes tumor growth by potentiating the RXFP1/cAMP/PKA/CREB axis, therefore positioning it as a promising therapeutic target for ovarian cancer. The graphical abstract was obtained from Stock ( https://www.storkapp.me/aifigure/app.php ).