Targeting SLC25A13 sensitizes melanoma to treatment and reduces tumor aggressiveness via metabolic rewiring

Therapy resistance is one of the main challenges for melanoma treatment, prompting the investigation of new therapeutic targets to elucidate novel therapeutic approaches and molecular insights. In this melanoma study, we have investigated the role of SLC25A13 which in humans encodes citrin, a mitochondrial carrier protein with a well-characterized function in metabolic diseases. We demonstrated that SLC25A13 upregulation in tumors is associated with poor survival in two large melanoma cohorts with long follow-up. Functional assays revealed that overexpression of SLC25A13 alters the level of key metabolites, leading to a metabolic syndrome-like state that is essential for the survival of metastatic melanoma cells. We propose that SLC25A13 functions as a key metabolic node promoting melanoma aggressiveness by enhancing proliferation, invasion, and tumor progression. Notably, we show that silencing Slc25a13 in aggressive mouse melanoma cells sensitizes them to both dacarbazine and MEK inhibition, highlighting its potential as a therapeutic target. Thus SLC25A13 is a key biomarker and a promising target for overcoming therapy resistance in metastatic melanoma.