Hydrogen sulfide inhibits neuroinflammation following cerebral ischemia/reperfusion injury via regulating glial polarization.

Hydrogen sulfide (H2S), an endogenous gasotransmitter, exerts potent anti-neuroinflammatory effects. Both endogenous and exogenous H2S attenuate cerebral ischemia/reperfusion (I/R) injury by suppressing neuroinflammatory responses. Microglia play a pivotal role in post-ischemic neuroinflammation. Upon activation, microglia polarize toward either the pro-inflammatory M1 phenotype or the anti-inflammatory M2 phenotype. The progression of neuroinflammation is closely associated with M1 polarization, while H2S has been demonstrated to inhibit M1 polarization and promote the protective M2 phenotype. Similarly, astrocytes undergo phenotypic transformation following ischemic stroke, with A1 reactive astrocytes exacerbating neuronal injury and A2 reactive astrocytes exerting neuroprotective effects. Our previous studies have shown that both endogenous and exogenous H2S promote astrocytic polarization toward the neuroprotective A2 phenotype. This review provides a comprehensive overview of ischemic stroke and the anti-neuroinflammatory effects of H2S and its donors in cerebral I/R injury, with particular emphasis on their roles in regulating microglial and astrocytic polarization toward neuroprotective phenotypes. Additionally, we discuss the intracellular signaling pathways involved in H2S-mediated suppression of neuroinflammation. Collectively, this review highlights the therapeutic potential of H2S donors as novel agents for the treatment of cerebral I/R injury. We propose that H2S donors exert their neuroprotective effects primarily through coordinated regulation of microglial and astrocytic polarization toward anti-inflammatory phenotypes, and that this dual-cell targeting strategy represents a viable therapeutic approach for cerebral I/R injury.