The latest research of the World Health Organization (WHO) reveals that stroke afflicts over 15 million people globally each year. Tragically, 6 million of these individuals succumb to death and another 5 million are left permanently disabled [1,2]. It is crucial to distinguish between the two major types of stroke: ischemic and hemorrhagic [3,4]. Cerebral ischemia, commonly referred to as ischemic stroke (IS), comprises nearly 85 % of all stroke cases and often results in disability and cognitive impairment, significantly influencing the patient's quality of life [5]. This condition is characterized by acute ischemia in specific brain regions, triggering various forms of cell death such as necrosis, apoptosis, ferroptosis, and pyroptosis [6,7]. Unfortunately, effective clinical treatments for cerebral ischemic stroke are currently limited, and the restoration of cerebral blood circulation can exacerbate the condition by causing cerebral ischemia-reperfusion injury (CIRI) [[8], [9], [10]]. Given the grave outcomes associated with cerebral ischemia, it is imperative to swiftly evaluate risks and promptly initiate a well-considered therapeutic strategy, incorporating robust neuroprotective measures, to effectively address this neurological emergency.

IS/cerebral ischemia results in the death or damage of neuronal cells, leading to enduring impairments in sensory perception, behavior, and memory (Fig. 1). As one of the most abundant excitatory neurotransmitter in the brain, glutamate plays a pivotal role in the excitotoxicity triggered by cerebral ischemia. Reduced ATP levels and malfunctioning glutamate transporters increase neuronal excitability, resulting in glutamate accumulation in the synaptic cleft. This accumulation leads to N-methyl-d-aspartate receptor overactivation, causing excessive calcium influx and subsequent neuronal dyshomeostasis [[11], [12], [13]]. Calcium overload activates calpain, inducing lysosomal-mediated apoptosis and necroptosis by cleaving apoptosis-regulating proteins. Additionally, cerebral ischemia upregulates death receptor ligands and stress-activated protein kinase, contributing to neuronal cell death pathways [[14], [15], [16], [17]]. Reperfusion post-ischemia exacerbates damage via excessive reactive oxygen species (ROS) formation, immune system activation, and pro-inflammatory cytokine release due to BBB disruption. Pro-inflammatory cytokines further increase ROS, reactive nitrogen species (RNS), cyclooxygenase-2, and inducible nitric oxide synthase (iNOS), exacerbating neuronal death [[18], [19], [20], [21], [22]]. Furthermore, impaired axon regeneration, mediated by chondroitin sulfate proteoglycans released by astrocytes, also contributes significantly to neuronal cell death post-cerebral ischemia. These molecules hinder axonal regeneration and neuronal survival by activating the RhoA/Rock pathway. Moreover, some studies have reported that myelin-associated glycoproteins hinder axonal regeneration and sprouting following cerebral ischemia [[23], [24], [25], [26]]. A comprehensive understanding of the pathological mechanisms of cerebral ischemia-induced brain damage is crucial for developing targeted treatment strategies, precisely intervening in specific biological events during disease progression, and providing a solid theoretical basis for the development of new treatment methods and interventions.