NETosis in ischemic stroke: Mechanisms, implications, and therapeutic prospects

Ischemic stroke remains a major global health burden, with secondary mechanisms of injury playing a critical role in initiation and progression of long-term neurological outcomes. Among these, the formation of neutrophil extracellular traps (NETosis) has gained significant traction as a key process that links innate immune activation with thrombotic and inflammatory damage in stroke. Shortly after the onset of cerebral ischemia, neutrophils rapidly infiltrate the affected tissue and undergo NETosis in response to Damage Associated Molecular Pattern (DAMPs) and inflammatory cues, releasing NET structures that interact with platelets, endothelial cells, and coagulation pathways. These NET components promote thrombus formation, enhance its structural stability, and confer resistance to fibrinolytic therapies, all while aggravating blood-brain barrier (BBB) breakdown, neuronal injury, and downstream neuroinflammatory cascades disturbing gut-brain axis and post stroke recovery. Clinical and pre-clinical investigations have shown that NET-related markers such as citrullinated histone H3, Myeloperoxidase (MPO)-DNA complexes, and circulating cell-free DNA are closely associated with stroke severity, infarct burden, and poorer clinical recovery, supporting their use as potential prognostic indicators. Experimental strategies aimed at inhibiting NET formation or accelerating its dissolution, including DNase-I administration, Peptidyl arginine deiminase 4 (PAD4) inhibition, and blockade of MPO activity, have demonstrated neuroprotective effects by reducing infarct size, preserving BBB function, and enhancing functional outcomes in animal models. Despite these encouraging findings, translating NET-targeted therapies into clinical practice remains complex due to the diversity of patient profiles and comorbidities that are weighing down translation efforts. This review highlights the central contribution of NETosis to stroke-related thrombosis, BBB disruption, and sustained inflammation, while emphasising the evolving potential of NET-focused interventions as future therapeutic tools in Ischemic stroke.