Necroptosis and the RIPK1-RIPK3-MLKL pathway in chronic kidney disease: mechanisms, crosstalk, and therapeutic opportunities.

Chronic kidney disease (CKD) is a prevalent global health concern with a high worldwide prevalence rate. It is defined by a steady deterioration in renal function, which causes toxins and metabolic waste to build up and cause systemic problems and multi-organ failure. The development and progression of CKD are influenced by a number of pathogenic factors, such as diabetes mellitus, hypertension, glomerulonephritis, and exposure to nephrotoxic chemicals. However, the precise underlying mechanisms remain incompletely understood. Necroptosis, a well-studied form of regulated cell death, is primarily mediated by the receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) signaling complex. Understanding necroptosis provides new avenues for therapeutic modulation of cillnehronic kidney disease, linking regulated cell death to fibrosis and inflammation. RIPK3 expression is upregulated up to five-fold in experimental CKD models, underscoring its pathogenic significance. The definition, key molecular mechanisms, and most current advancements in pharmacological research pertaining to necroptosis are all comprehensively summarized in this article. This review provides mechanistic insights into necroptosis in CKD and highlights therapeutic targets for future translational research.