A CEBPB/TYMP/GDF15 signaling axis mediates tumor growth and cisplatin resistance in bladder cancer.

Cisplatin-based chemotherapy remains the standard treatment for muscle-invasive bladder cancer (BC), yet resistance significantly limits its long-term efficacy. Reliable biomarkers for prognosis and therapeutic guidance are also lacking. Here, we identify thymidine phosphorylase (TYMP) as an independent prognostic risk factor that promotes BC progression and mediates cisplatin resistance. Bioinformatic analyses of TCGA and GEO datasets revealed elevated TYMP expression in BC tissues, correlating with poor patient outcomes. Functional studies in UMUC3, T24, and MB49 cell lines, as well as in syngeneic mouse models, demonstrated that TYMP knockdown suppressed BC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while enhancing cisplatin sensitivity. Pharmacological inhibition of TYMP using TAS-102 significantly augmented cisplatin-induced cytotoxicity in vivo. Mechanistically, the transcription factor CEBPB directly bound to and activated the TYMP promoter, thereby upregulating GDF15 expression and driving tumor growth and chemoresistance. TYMP expression positively correlated with both CEBPB and GDF15 levels in public datasets. Collectively, our findings define a CEBPB/TYMP/GDF15 signaling axis that fosters BC progression and cisplatin resistance and highlight TYMP as a novel prognostic biomarker and potential therapeutic target, with TAS-102 offering a promising strategy for overcoming cisplatin resistance.