Metabolic Collapse in Acute CNS Injury: A Spatiotemporal Framework Linking Redox Failure, Ferroptosis, and Neurovascular Dysfunction

Significance: Acute central nervous system (CNS) injuries impose a significant global burden. Microsurgical decompression effectively stabilizes primary anatomy. However, it often fails to stop the complex biochemical cascades of secondary neurodegeneration. There is a critical need to bridge the gap between anatomical preservation and functional recovery. Strong preclinical evidence indicates that delayed bioenergetic failure within the injury microenvironment heavily dictates long-term outcomes. Recent Advances: We synthesize the ARFE (autophagy-reactive oxygen species-ferroptosis-edema) axis as a mechanistic framework delineating the pathological continuum from subcellular failure to macroscopic tissue edema. In this irreversible cascade, adenosine triphosphate depletion blocks autophagic flux, forcing ferritinophagy-driven iron release and lipid peroxidation, while succinate accumulation locks microglia in metabolic collapse. Critical Issues: A translational gap persists because mechanical hematoma evacuation does not inherently reverse the metabolic cascades driving secondary injury. Current single-target modalities fail because they do not account for the evolving metabolic microenvironment, leading to unchecked inflammation and cell death despite successful surgical intervention. Future Directions: We propose a paradigm shift from single-target modalities to “spatiotemporal metabolic engineering.” This strategy synchronizes interventions with metabolic logic. Hyperacute treatments focus on redox containment to neutralize iron. Acute phases prioritize immune-metabolic reprogramming for inflammation. Finally, subacute stages aim for bioenergetic reconstruction to support axonal regrowth. Antioxid. Redox Signal. 00, 000–000.