EXPRESS: Thirty Years Later: Revisiting the Glial Failure Hypothesis as the Homeostatic Organizing Principle of...

Thirty years after the glial failure hypothesis was proposed, ischemic neuronal death still lacks a unifying mechanism. Here we revisit the hypothesis in light of evidence positioning astrocytes as central regulators of metabolic, ionic, and vascular homeostasis, unifying mechanisms often considered independently in ischemic injury. Early astrocytic responses, including adenosine-mediated synaptic suppression, may transiently protect tissue by reducing energetic demand. Progressive glial dysfunction, however, drives spontaneous spreading depolarizations and impairs their termination, creating a bifurcation toward immediate or delayed neuronal terminal depolarization depending on energetic capacity. Thus, glial failure emerges as the upstream disturbance linking metabolic compromise to neuronal injury.