PAQR3 Promotes Diabetic Tubulointerstitial Fibrosis by suppressing STUB1-mediated NOX4 ubiquitination.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease, and tubulointerstitial fibrosis (TIF) represents its final pathological hallmark. Progestin and adipoQ receptor 3 (PAQR3) has been implicated in metabolism and inflammation, but its role in DKD remains largely unexplored. Here, we report that PAQR3 expression is markedly upregulated in the kidneys of STZ-induced diabetic mice and in high glucose-stimulated NRK-52E tubular epithelial cells, correlating with the onset of tubular epithelial-mesenchymal transition (EMT) and fibrosis. Functional studies demonstrated that PAQR3 overexpression via AAV delivery in db/db mice significantly exacerbated renal dysfunction, fibrotic lesions, and EMT, whereas PAQR3 knockdown in cultured tubular cells attenuated the EMT phenotype. Mechanistically, PAQR3 selectively increased NOX4 protein levels without affecting its mRNA expression, leading to enhanced ROS production and oxidative stress. Notably, PAQR3 suppressed STUB1-mediated NOX4 ubiquitination, thereby stabilizing NOX4 protein. Collectively, these findings suggest that PAQR3 modulates NOX4 protein stability by suppressing its ubiquitination and the PAQR3-STUB1-NOX4 axis may contribute to TIF progression in DKD.