Metabolic syndrome necroptosis: disease implications and therapeutic targeting.
Necroptosis is a regulated form of cell death characterized by receptor-interacting protein kinase (RIPK) activation, leading to necrosome formation and subsequent membrane rupture. Increasing evidence indicates that necroptosis contributes to metabolic syndrome (MetS) by promoting tissue inflammation, insulin resistance, and metabolic dysfunction. The molecular mechanisms underlying necroptosis in MetS primarily involve activation of the RIPK1-RIPK3-MLKL axis, particularly in metabolically active tissues such as skeletal muscle, liver, adipose tissue, and pancreatic β-cells. Although numerous experimental studies have linked necroptosis to metabolic inflammation and organ injury, a systematic synthesis of its mechanistic roles, biomarker relevance, and translational potential in MetS remains limited. This review summarizes current evidence on the molecular regulation of necroptosis in MetS, its involvement in disease progression across multiple organs, and emerging diagnostic, prognostic, and theragnostic biomarkers. In addition, this review discusses therapeutic strategies targeting necroptosis and critically evaluates their translational challenges. By integrating mechanistic and translational perspectives, this review aims to provide a balanced framework for understanding the role of necroptosis in MetS and to highlight key knowledge gaps that warrant further investigation.