By integrative multi-omics analyses in tRCC cell lines and patient tumors together with loss and gain of function experiments, we found broad binding of TFE3-fusion proteins at active promoters and identified a core set of target genes involved in multiple pathways, including oxidative metabolism (OxPhos) and ferroptosis. Here, TFE3 is linked to renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.