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A stroke begins with abrupt interruption of cerebral blood flow, most commonly due to arterial occlusion in ischemic stroke, leading to acute deprivation of oxygen and glucose and rapid collapse of neuronal ATP production, since neurons rely almost exclusively on mitochondrial oxidative phosphorylation to maintain ionic gradients¹. This energy failure disables Na⁺/K⁺ ATPases, causing membrane depolarization, calcium influx via voltage-gated and NMDA receptors, and pathologic glutamate release that drives excitotoxic neuronal injury¹ ². Calcium overload activates calpains, phospholipases, endonucleases, and PARP, damaging cytoskeletal proteins, membranes, and DNA². Mitochondrial calcium accumulation prompts reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential, cytochrome c release, and activation of apoptosis pathways, while severe energy deficit triggers necrosis¹ ². Astrocytes initially buffer extracellular glutamate and K⁺ but become overwhelmed and undergo reactive gliosis that alters neurovascular homeostasis³. Microglia polarize into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes after ischemia, releasing cytokines such as TNF-α and IL-1β that amplify secondary injury or support recovery depending on the context⁴. Endothelial cells become hypoxic and permeable, compromising the blood–brain barrier and permitting infiltration of peripheral immune cells, which further exacerbates inflammation and oxidative damage⁵. On the molecular level, hypoxia stabilizes HIF-1α, which promotes adaptive gene programs (glycolysis, VEGF-mediated angiogenesis) but, under prolonged or severe ischemia, also induces pro-apoptotic and acidotoxic pathways that worsen injury⁶. Emerging evidence highlights ferroptosis, an iron-dependent, lipid peroxidation-driven form of programmed cell death, as a critical contributor to ischemic neuronal death, interlinked with glutathione depletion, dysregulated iron metabolism, and oxidative stress⁷^,⁸. Together, stroke unfolds as a complex cellular and molecular drama involving bioenergetic failure, ionic dysregulation, oxidative stress, inflammatory signaling, and regulated cell-death mechanisms, where understanding these pathways is key to identifying therapeutic targets like excitotoxic cascade inhibitors, antioxidants preserving mitochondrial function, ferroptosis modulators, and anti-inflammatory strategies¹^,⁷.

References:

Dong, H. (2024). Recent advances in potential therapeutic targets of ferroptosis for ischemic stroke. Molecular Medicine Reports.

Gowtham, A., Chauhan, C., Rahi, V. R., & Kaundal, R. K. (2024). An update on the role of ferroptosis in ischemic stroke: From molecular pathways to neuroprotection. Expert Opinion on Therapeutic Targets, 28(12), 1149–1175.

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Tian, X., et al. (2024). Progress of ferroptosis in ischemic stroke and therapeutic targets. Cellular and Molecular Neurobiology.

Wikipedia contributors. (2025, July). Brain ischemia. Wikipedia. Retrieved from en.wikipedia.org/wiki/Brain_ischemia