Nuclear IDH3A Drives Transcriptional Programs in Melanoma via the YBX1-JUN/FOS Axis

Isocitrate dehydrogenase 3 alpha (IDH3A) is a key rate-limiting enzyme in the tricarboxylic acid (TCA) cycle, traditionally associated with cellular energy metabolism. However, its role in cancer remains incompletely understood. Here, we demonstrate that IDH3A is significantly overexpressed in melanoma, primarily due to DNA copy number amplification. Metabolomic analysis revealed that IDH3A overexpression enhanced multiple biosynthetic intermediates, including G6P, F6P, DHAP, and 6-phosphogluconate, indicating metabolic reprogramming toward anabolic processes without significantly affecting ATP or lactate production. Intriguingly, IDH3A localizes to the nucleus in melanoma cells and promotes tumorigenesis independent of its dehydrogenase activity. Nuclear IDH3A interacts with transcription factor YBX1, enriching at promoter regions of oncogenes such as c-FOS and c-JUN, thereby suppressing apoptosis and promoting tumor growth. Furthermore, we identify NONO as a nuclear chaperone that facilitates the nuclear localization of IDH3A through direct interaction, primarily involving NONO amino acids Q166 and S207. Disruption of NONO impairs IDH3A nuclear translocation and mitigates its tumor-promoting function. Collectively, our findings uncover a noncanonical role of IDH3A as a nuclear regulator of transcription via YBX1, offering novel insight into metabolic enzyme reprogramming in melanoma.