Abstract: Stroke, particularly ischemic stroke, is the leading cause of long-term disability and mortality worldwide. It occurs due to the occlusion of the cerebral arteries, which significantly reduces the delivery of blood, oxygen, and essential nutrients to brain tissues. This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death. Recent studies have clarified the multifactorial pathogenesis of ischemic stroke, highlighting the roles of energy failure, excitotoxicity, oxidative stress, neuroinflammation, and apoptosis. This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke. Additionally, we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke, including the interplay of apoptosis, autophagy, pyroptosis, ferroptosis, and necrosis, which collectively influence neuronal fate. We also discussed advancements in neuroprotective therapeutics, encompassing a range of interventions from pharmacological modulation to stem cell-based therapies, aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke. Despite these advancements, challenges remain in translating mechanistic insights into effective clinical therapies. Although neuroprotective strategies have shown promise in preclinical models, their efficacy in human trials has been inconsistent, often due to the complex pathology of ischemic stroke and the timing of interventions. In conclusion, this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia. It sheds light on cutting-edge advancements in potential neuroprotective therapeutics, underscores the promise of regenerative medicine, and offers a forward-looking perspective on potential clinical breakthroughs. The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.

Key words: apoptosis, cerebral infarction, clinical trial, inflammation, ischemic stroke, mitochondria, neurons, neuroprotection, oxidative stress, pathophysiology, stem cells