Reciprocal regulation between JOSD2 and CREB1 drives aerobic glycolysis and progression of renal cell carcinoma.

Dysregulated aerobic glycolysis represents a defining metabolic feature of renal cell carcinoma (RCC), yet the regulatory networks driving this metabolic shift remain incompletely elucidated. In the present study, we found that the deubiquitinase Josephin domain-containing protein 2 (JOSD2) is necessary for both glycolytic and proliferative activities in RCC. Furthermore, JOSD2 is significantly upregulated in RCC and its high expression correlates with poor clinical outcomes. Functional studies demonstrated that JOSD2 enhances RCC cell growth, metastatic capacity, and glycolytic activity in vitro and in vivo. Mechanistically, JOSD2 directly interacts with the transcription factor CREB1 and prevents its proteasomal degradation by removing K48-linked polyubiquitin chains, thereby stabilizing the CREB1 protein. Meanwhile, CREB1 transcriptionally upregulates JOSD2 by binding to its promoter, forming a reciprocal regulatory circuit between the two molecules. Reciprocal activation between JOSD2 and CREB1 leads to increased expression of key glycolytic regulators, including GLUT1, HK2, and PFKP, thereby driving metabolic reprogramming in RCC cells. Importantly, the tumor-promoting functions of JOSD2 were found to be largely dependent on CREB1 activity. Together, these results support a role for the JOSD2-CREB1 reciprocal axis in glycolysis-associated RCC progression and suggest its potential prognostic and therapeutic relevance.