The Inflammatory Cell Death in Diabetic Kidney Disease: Integrating Multifactorial Mechanisms into Novel Therapeutics
Bin Fang, Wei Huang, Sijia Du, Hao Yu, Fang-Fang He, Chun Zhang
Abstract
In addition to apoptosis, inflammatory cell death modalities-including pyroptosis, necroptosis, ferroptosis, NETosis, and the integrated paradigm of PANoptosis-are now established as critical drivers of diabetic kidney disease (DKD) pathogenesis. This review summarizes how key inflammatory cell death molecular mediators-such as the NLRP3 inflammasome, the RIPK1/RIPK3/MLKL axis, executioner caspases, and gasdermin-D (GSDMD)-orchestrate the death of renal cells (podocytes, tubular cells, mesangial cells, endothelium), thereby propagating inflammation and fibrosis. Preclinical studies have demonstrated the efficacy of agents targeting these pathways, highlighting their therapeutic potential. Key challenges include achieving cell type-specific targeting, overcoming redundancy among cell death pathways, and improving the translational applicability of current models. Emerging solutions include the development of precise biomarkers, kidney-targeted delivery systems, and combination therapies that concurrently target multiple cell death axes. This review synthesizes evidence establishing inflammatory cell death as a cornerstone of DKD pathology and provides a conceptual framework to guide future research and therapeutic innovation.