USP43-mediated HSPA8 deubiquitination alleviates diabetic kidney disease.

Diabetic kidney disease (DKD) involves lipid metabolism dysfunction, leading to renal lipotoxicity. HSPA8 suppresses lipid accumulation by inhibiting SREBP pathway activation, but its degradation mechanism in DKD remains unclear. Here, we identified USP43 as a key regulator that stabilizes HSPA8 by removing K48-linked polyubiquitination at Lys597/601. In DKD mice, HSPA8 mutants (K597R/K601R) reduced lipid deposition and improved renal function compared to wild-type HSPA8. Under high glucose, AKT phosphorylates USP43, promoting its binding to 14-3-3β/ε and weakening USP43-HSPA8 interaction. This accelerates HSPA8 degradation, enhancing SREBP-mediated lipid accumulation and DKD progression. Our findings reveal that AKT-induced USP43 phosphorylation disrupts HSPA8 stability, exacerbating renal lipotoxicity. This study uncovers the AKT-USP43-HSPA8 axis in DKD pathogenesis, providing a potential therapeutic strategy targeting HSPA8 stabilization.