Stroke, also called cerebral vascular accident (CVA), is a common cerebrovascular disorder that usually occurs suddenly, resulting in disseminated and regional damage in the brain [1], [2], [3]. Globally, stroke has a high incidence of morbidity, mortality, and disability, with approximately 16.9 million cases of first stroke and 6 million deaths caused by stroke every year [4], [5], [6], [7]. About half of the survivors will suffer physical disability or cognitive impairment following stroke, and about 20 % need hospitalization [8], [9]. Stroke is classified into two types: ischemic stroke (70–80 % of all strokes, because of the disruption of blood supply) and hemorrhagic stroke (nearly 10–20 %, because of bleeding) [10], [11]. Ischemic stroke is a complex event of the central nervous system (CNS) due to temporary or permanent arterial occlusion, which can cause permanent neurological damage [12]. The treatment option for reducing brain damage after stroke is still early restoration of cerebral blood supply [13]. Treatment with intravenous recombinant human tissue plasminogen activator (rtPA) remains one of the limited well-established therapies for ischemic stroke [14], [15], [16]. However, rtPA has a narrow treatment window of about 4.5 h, and only about 4 % of stroke patients can benefit from it [17], [18]. Therefore, there is an urgent need to explore the novel targets of ischemic stroke to seek new treatment strategies.

Stroke is a serious neurological disorder that poses a threat to millions of people and has become a serious social and clinical burden worldwide [19]. As a type of stroke, ischemic stroke occurs due to inadequate blood and oxygen supply of the cerebral blood vessels [20], [21]. Insufficient blood supply disrupts the homeostasis of the intracellular environment in brain cells and leads to various harmful responses, including oxidative stress, apoptosis, and inflammation, thus resulting in irreparable brain injury [22], [23]. Among the various related mechanisms of cerebral ischemia, inflammation is a vital factor in ischemic brain damage [24], [25]. The inflammatory reaction in the CNS is featured by the microglial activation and infiltration of inflammatory factors that are generated and secreted from affected neurons, astrocytes, microglia, and so on [26], [27]. Once activated, microglia and astrocytes exhibit two types: the pro-inflammatory phenotype (M1 and A1) and the anti-inflammatory phenotype (M2 and A2) [28]. The continued presence of the pathological condition leads to the transformation of the M1/A1 phenotype into the M2/A2 phenotype [28]. After ischemic stroke, the activation of microglia leads to the generation of pro-inflammatory factors, including IL-1β, IL-6, and TNF-α, which may cause further brain injury[27], [29].In summary, there exists a strong correlation between inflammation and stroke, and the elucidation of this key issue can provide novel and reliable therapeutic targets for stroke [30].

In recent years, it has been demonstrated that pyroptosis, a novel style of programmed cell death related to inflammation, plays a key role in the pathogenesis of ischemic stroke [31]. Following the activation of the inflammasome, the intracellularly GSDMD-induced pores disrupt the electrolyte balance, ultimately releasing pro-inflammatory cytokines, such as IL-1β and IL-18, thus exacerbating inflammatory pathology, finally leading to pyroptosis [32]. Thus, there is a strong connection between pyroptosis and inflammation [33]. There is a close relationship among NLRP3 inflammasome-induced microglial pyroptosis, brain inflammation and functional restoration following stroke [34]. The role of pyroptosis induced by inflammation in brain damage after ischemic stroke has received increasing attention. It was reported that melatonin-treated exosomes significantly attenuated neurological dysfunction by inhibiting microglial pyroptosis following ischemic stroke [35]. Moreover, dendrobium alkaloids could reduce neuronal death by suppressing pyroptosis, thereby alleviating brain ischemic damage in mice [36]. Therefore, inhibition of pyroptosis might become a new strategy for the treatment of stroke. A greater understanding of the molecular mechanisms of pyroptosis in ischemic stroke may provide a theoretical foundation for novel stroke therapies.

This review elaborates on the effect of pyroptosis-related proteins in ischemic stroke, including inflammasomes, caspases, and inflammatory factors. Moreover, we have summarized the current approaches to treat ischemic stroke by targeting pyroptosis. Insight into the role of pyroptosis will benefit the development and clinical translation of new and promising therapeutic approaches in ischemic stroke.