NUPR1 Inhibition Prevents Mitotic Catastrophe: A Novel Therapeutic Strategy for Podocyte Injury in Diabetic Kidney Disease

Mitotic catastrophe (MC) is a frequent and decisive event that drives podocyte loss in diabetic kidney disease (DKD). The molecular mechanisms underlying this process are not fully understood. However, recent studies have identified nuclear protein 1 (NUPR1) as a key regulator of MC in podocytes. NUPR1 was found to be significantly upregulated in podocytes from human DKD biopsies and its expression level positively correlated with albuminuria. Overexpression of NUPR1 in DKD mice exacerbated podocyte injury and increased albuminuria. Functional analyses revealed that NUPR1 promotes aberrant podocyte entry into the G2/M phase, thereby triggering MC and aggravating renal injury. The mechanism underlying this process involves the recruitment of BRD2 to the Cyclin B2 promoter, forming a transcriptional complex that enhances Cyclin B2 expression. Genetic or pharmacological disruption of this NUPR1-BRD2 interaction suppressed Cyclin B2 expression, prevented MC, and preserved podocyte numbers. Furthermore, pharmacological inhibition of NUPR1 using ZZW-115 significantly alleviated albuminuria, reduced mesangial matrix expansion, and mitigated podocyte injury in DKD mice, without impacting systemic glucose levels. These findings suggest that the NUPR1-BRD2/Cyclin B2 axis is a critical molecular driver of podocyte MC and establish NUPR1 as a promising therapeutic target for slowing DKD progression.