USP15 stabilizes c-Myc to drive sunitinib resistance by suppressing cuproptosis in clear cell renal cell carcinoma.

Cuproptosis, a recently characterized form of mitochondrial-dependent cell death triggered by copper accumulation, remains unexplored in clear cell renal cell carcinoma (ccRCC) and sunitinib resistance. Here, we reveal that the deubiquitinase USP15 suppressed cuproptosis and drove sunitinib resistance in ccRCC. Mechanistically, USP15 stabilized c-Myc through K48-linked deubiquitination at K143 and K289, leading to transcriptional upregulation of PDK1, PDK3, and PDK4 and subsequent repression of DLAT expression and pyruvate dehydrogenase, thereby conferring resistance to cuproptosis. Conversely, the E3 ligase MYCBP2 promoted K48-linked ubiquitination and degradation of c-Myc, antagonizing USP15 function. Sunitinib treatment induced features of cuproptosis, while USP15 upregulation in resistant cells suppressed these effects. USP15 depletion or elesclomol (ES)-Cu/disulfiram (DSF)-Cu restored sunitinib sensitivity both in vitro and vivo without systemic toxicity. Collectively, our findings identify USP15 as a critical regulator of cuproptosis and sunitinib resistance and highligh cuproptosis activation as a promising strategy to overcome tyrosine kinase inhibitor (TKI) resistance in ccRCC.