Transcription factor EN1 governs a lipogenic USP18-ACLY axis to drive bladder cancer malignancy.

Bladder cancer (BLCA) is a lethal malignancy with limited therapeutic options. The role of the transcription factor Engrailed-1 (EN1) in BLCA metabolic reprogramming was previously unknown. Our study demonstrates that EN1 is significantly overexpressed in BLCA, correlating with poor patient survival and driving tumor progression. Mechanistically, EN1 transcriptionally upregulates the deubiquitinase USP18. USP18, in turn, prevents the proteasomal degradation of ATP-citrate lyase (ACLY), thereby stabilizing this gatekeeping enzyme to enhance de novo lipogenesis. Crucially, we identified the FDA-approved drug Udenafil as a candidate EN1-targeting compound. Udenafil suppressed the USP18/ACLY axis and inhibited BLCA progression in preclinical models. This study defines the EN1-USP18-ACLY axis as a master regulator of lipogenesis and a promising therapeutic target in BLCA, supporting the repositioning of Udenafil as a potential treatment strategy.