USP43 stabilizes c-Myc to promote glycolysis and metastasis in bladder cancer. This study identifies USP43 as a deubiquitinase that regulates glycolytic metabolism and c-Myc transcriptional activity in bladder cancer (BLCA). USP43 stabilizes c-Myc by deubiquitinating it at K148 and K289, preventing its degradation through the ubiquitin-proteasome pathway. This stabilization enhances c-Myc activity, which in turn promotes glycolysis and metastasis in BLCA. USP43 also interferes with FBXW7 access to c-Myc, further stabilizing it. The study reveals a positive feedback loop between USP43 and c-Myc in BLCA, where USP43 stabilizes c-Myc, which then activates USP43 transcription. This loop contributes to the malignant behaviors of BLCA, including aberrant glycolysis and c-Myc accumulation. USP43 is a potential therapeutic target for indirectly targeting glycolytic metabolism and the c-Myc oncoprotein, thereby enhancing the efficacy of bladder cancer treatment. The study also shows that c-Myc directly regulates USP43 transcription, indicating that USP43 is a direct target of c-Myc. These findings highlight the importance of USP43 in the progression of BLCA and suggest that targeting USP43 could be a promising strategy for treating this disease.USP43 stabilizes c-Myc to promote glycolysis and metastasis in bladder cancer. This study identifies USP43 as a deubiquitinase that regulates glycolytic metabolism and c-Myc transcriptional activity in bladder cancer (BLCA). USP43 stabilizes c-Myc by deubiquitinating it at K148 and K289, preventing its degradation through the ubiquitin-proteasome pathway. This stabilization enhances c-Myc activity, which in turn promotes glycolysis and metastasis in BLCA. USP43 also interferes with FBXW7 access to c-Myc, further stabilizing it. The study reveals a positive feedback loop between USP43 and c-Myc in BLCA, where USP43 stabilizes c-Myc, which then activates USP43 transcription. This loop contributes to the malignant behaviors of BLCA, including aberrant glycolysis and c-Myc accumulation. USP43 is a potential therapeutic target for indirectly targeting glycolytic metabolism and the c-Myc oncoprotein, thereby enhancing the efficacy of bladder cancer treatment. The study also shows that c-Myc directly regulates USP43 transcription, indicating that USP43 is a direct target of c-Myc. These findings highlight the importance of USP43 in the progression of BLCA and suggest that targeting USP43 could be a promising strategy for treating this disease.