Therapeutic Implications of Cell Death Pathways Across the Course of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, resulting in paralysis and limited survival. Multiple regulated cell death pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, lysosomal cell death, autophagy-dependent cell death, NETosis, and other emerging cell death modalities, have been implicated in ALS, but their mechanistic interactions and relative contributions remain poorly understood. This knowledge gap has hindered the development of effective therapies. Better experimental models are needed to dissect these pathways. This review summarizes current knowledge on the roles of cell death pathways in ALS. A tiered framework (M1-M4) is applied to critically evaluate data from human postmortem tissue, patient-derived cells, and animal models, ranking studies according to their relevance to human disease. Potential crosstalk among these pathways is further examined. It is also proposed that the relative contribution of specific cell death pathways may shift with disease progression, although this hypothesis requires longitudinal validation. To integrate this dynamic perspective, cell death pathway activities are hypothetically aligned with the King's clinical staging system. This stage-informed framework is presented as a conceptual model intended to generate hypotheses rather than to serve as a validated clinical algorithm. The model distinguishes established therapies from preclinical and exploratory strategies. Future research should prioritize the development of human-relevant model systems, the identification of longitudinal biomarkers of cell death, and the implementation of rigorously designed combination trials. These efforts may ultimately enable more precise, stage-appropriate therapeutic strategies for ALS.