Deubiquitinating enzymes in kidney diseases: Molecular mechanisms, pathological roles and therapeutic opportunities (Review)

Abstract

The ubiquitin-proteasome system maintains cellular protein turnover and quality control through the coordinated action of ubiquitin ligases and deubiquitinating enzymes (DUBs). While the functions of E3 ubiquitin ligases have been extensively investigated in renal disease, the ~100 human DUBs distributed across seven structurally distinct families have recently emerged as important regulators of renal physiology and pathology. The present review organizes current knowledge of DUB-mediated regulation in kidney disease around functional themes rather than individual disease categories. The present review discusses how DUBs regulate inflammatory signaling, TGF-β-mediated fibrotic responses, epithelial-to-mesenchymal transition (EMT), mitochondrial homeostasis, multiple forms of programmed cell death, podocyte homeostasis, and oncogenic pathways in renal cell carcinoma. Several DUBs, including A20 (TNFAIP3), CYLD, USP25 and OTUD5, restrain inflammation and fibrosis, whereas USP11, OTUD1, and USP22 promote disease progression through substrate stabilization. The translational landscape of DUB inhibitors, PROTAC degraders, and the DUBTAC platform for targeted protein stabilization, along with the selectivity and delivery challenges that remain, were discussed. Key unanswered questions, including cell-type-specific DUB functions, ubiquitin chain linkage context, and the therapeutic window for DUB modulation in the kidney, are outlined as priorities for future investigation.