TRIM38 alleviates the pathogenesis of diabetic nephropathy by suppressing NF-κB activation via inducing RIPK1 degradation.

Diabetic nephropathy (DN), a major microvascular complication of diabetes, remains a leading cause of end-stage renal disease. Tripartite motif protein 38 (TRIM38), a member of the TRIM family, plays critical roles in apoptosis, innate immunity, and inflammatory processes. Data of GEO database shows that TRIM38 is notably increased in the renal tubules of patients with DN. However, its functional significance in DN pathogenesis remains unexplored. In this study, streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-treated HK-2 cells were employed to mimic DN conditions. Our results demonstrated that TRIM38 expression was significantly upregulated in renal tissues of DN patients, STZ-induced diabetic mice, and HG-stimulated HK-2 cells. Functionally, TRIM38 overexpression ameliorated renal dysfunction in diabetic mice and preserved the NAD+/NADH balance, while attenuating oxidative stress and inflammatory responses. Mechanistically, TRIM38 overexpression suppressed the NF-κB signaling activation. Further analysis revealed that TRIM38 physically interacted with receptor-interacting protein kinase 1 (RIPK1) and promoted its ubiquitination and degradation, thereby inhibiting the NF-κB pathway activation. Rescue experiments confirmed that RIPK1 overexpression abolished the protective effects of TRIM38 overexpression on HG-treated HK-2 cells. Our study identifies TRIM38 as a novel modulator of DN progression that exerts its protective effects by targeting RIPK1 degradation and subsequent inhibition of NF-κB signaling. These findings provide new insights into the molecular mechanisms underlying DN and highlight TRIM38 as a potential therapeutic target for DN treatment.