Ferroptosis-Pyroptosis Crosstalk in Spinal Cord Injury: Molecular Mechanisms, Emerging Connectors, and Staged Therapeutic Perspectives.

Secondary injury after spinal cord injury (SCI) develops through intertwined oxidative, metabolic and inflammatory processes that engage several programmes of regulated cell death. Ferroptosis and pyroptosis are both implicated in experimental SCI, but their relationship across cellular compartments and injury phases remains incompletely understood. Ferroptotic injury is prominent in neurons, oligodendrocyte-lineage cells and vascular endothelium. Inflammasome-gasdermin signalling is concentrated mainly in microglia and infiltrating myeloid cells. Their partial cellular separation raises the possibility that coupling occurs through shared lesion stress and communication between neighbouring populations. This review examines how metabolic, redox and inflammatory disturbances shape ferroptosis-pyroptosis coupling across cells and over time, and distinguishes common upstream regulation from direct cross-pathway control. The emerging picture is one of context-dependent metabolic-inflammatory coupling, with the strength and direction of interaction likely to vary across lesion compartments and injury phases. Clinical translation will depend on identifying where and when each pathway is active and on developing biomarkers and treatment strategies matched to lesion biology.