From RIPK1 to Necroptosis: Pathogenic Mechanisms in Neurodegenerative Diseases

Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis, a newly identified mode of regulated cell death, represents a significant pathogenic mechanism in multiple neurodegenerative disorders. Substantial experimental evidence indicates that RIPK1 regulates necroptotic cell death pathways in both neuronal and glial cell populations through activation of the canonical RIPK3-MLKL signaling cascade, thereby exacerbating neuroinflammatory responses and accelerating neurodegenerative progression. The pathological relevance of this molecular pathway has been extensively validated across multiple major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Pharmacological interventions targeting RIPK1 or its downstream effectors-particularly RIPK3 and MLKL-have demonstrated significant efficacy in mitigating disease-associated pathological manifestations. This highlights the RIPK1 signaling axis as a promising therapeutic target for neuroprotective strategies. Consequently, thorough investigation of RIPK1-mediated necroptosis in neurodegenerative settings holds considerable translational potential. Such inquiry deepens mechanistic understanding of disease pathogenesis while accelerating the advancement of innovative therapeutic approaches with direct clinical relevance.