Integrated bioinformatics analysis uncovers TNFSF10 as a key panoptosis-related gene in diabetic tubular injury

Diabetic kidney disease (DKD) is a major cause of chronic kidney diseases. Panoptosis has emerged as a key contributor to renal injury. However, the specific panoptosis-related genes (PRGs) that drive diabetic tubular injury remain unknown. TNFSF10, a known regulator of apoptosis and inflammation, has been linked to podocyte injury in DKD, but its role in diabetic tubular injury remains unknown. To address this, we integrated weighted gene co-expression network analysis, machine learning algorithms, and clinical data from the Nephroseq database to identify PRGs associated with DKD. The biological function of the identified hub gene was further characterized by integrating single-cell and single-nucleus RNA sequencing data with analytical frameworks for cellular communication, trajectory inference, and regulatory network. In this study, we identified TNFSF10 as a conserved and robust hub PRG for DKD. TNFSF10 expression was significantly upregulated in DKD kidneys and inversely correlated with glomerular filtration rate. TNFSF10high kidneys exhibited elevated fibrosis and inflammation scores. scRNA/snRNA analysis revealed its predominant expression in injured proximal tubular cells. Importantly, TNFSF10+ proximal tubular cells showed transcriptomic signatures consistent with panoptosis activation and inflammatory signaling, along with enhanced ligand-receptor interactions with fibroblasts and immune cells. Consistently, TNFSF10 treatment induced cell death and increased the expression of multiple inflammatory genes in vitro. Collectively, our results suggest that TNFSF10 is associated with tubular injury and kidney fibroinflammation in DKD. These exploratory findings suggest it may represent a promising candidate for DKD, and further in vivo functional validation is required to confirm its diagnostic and therapeutic potential.