Deubiquitinase USP7 stabilizes the histone demethylase KDM5B and promotes the progression of renal fibrosis through the TSC1/mTOR axis.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays critical regulatory roles in multiple signaling pathways by preventing the ubiquitin-mediated degradation of its substrates. Dysregulated expression of USP7 is implicated in tumor progression; however, its role in renal fibrosis remains unclear. In the present study, USP7 was observed to be significantly upregulated in the kidneys of patients with chronic kidney disease (CKD), which correlated with fibrotic lesions and renal dysfunction. Both genetic depletion and pharmacological blockade of USP7 significantly attenuated fibroblast activation and extracellular matrix deposition in two mouse models of kidney fibrosis-unilateral ureteral obstruction and unilateral renal ischemia-reperfusion injury models, indicating a pro-fibrotic function of USP7. Mechanistically, intergrated proteomic sequencing and phosphoproteomic sequencing revealed that USP7 modulated the tuberous sclerosis complex 1 (TSC1)-mTOR pathway. USP7 knockdown restored TSC1 expression and inhibited mTOR activation. However, USP7 did not directly interact with TSC1; instead, it deubiquitinated and stabilized lysine-specific demethylase 5B (KDM5B), which subsequently reduced histone H3K4me3 modification at the Tsc1 promoter to repress its transcription. Conversely, the inhibition of USP7 promoted KDM5B degradation, thereby restoring TSC1 expression and suppressing mTOR-driven fibrogenesis. Thus, these findings identify USP7 as a critical promoter of renal fibrosis, acting at least in part through the KDM5B-TSC1-mTOR axis. This highlights USP7 as a potential therapeutic target for CKD.