A Narrative Review of Necroptosis in Neuromuscular Junction Disorders: Pathogenesis and Therapeutic Strategies

Necroptosis is a regulated and inflammatory form of cell death that has emerged as a key contributor to neuromuscular junction (NMJ) dysfunction. This narrative review aims to synthesize current evidence on the role of necroptosis in NMJ pathology and its potential therapeutic implications. First, we present the conceptual framework linking necroptosis to NMJ degradation, focusing on core mediators such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL). Second, we summarize the available evidence across NMJ compartments, including motor neurons, Schwann cells, and skeletal muscle. We also describe how necroptosis activation correlates with structural and functional deficits in conditions such as spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. Third, we examine the translational potential of targeting necroptosis, highlighting preclinical studies on RIPK1, RIPK3, and MLKL inhibitors. Although these findings suggest therapeutic value, current evidence is predominantly derived from animal models, and clinical applicability remains uncertain. Rigorous trials are needed to confirm the safety and efficacy of these treatments. Understanding necroptosis as a shared mechanism across NMJ components may inform future strategies to preserve neuromuscular function.