Mol Neurobiol. 2026 Jun 15;63(1):694. doi: 10.1007/s12035-026-05999-2.
ABSTRACT
Ischemic stroke, a major contributor to global disability and mortality, results from the disruption of cerebral blood flow. The efficacy of recanalization therapy, the primary intervention for ischemic stroke, is often compromised by cerebral ischemia/reperfusion (I/R) injury. A critical factor in this pathological process is microglial polarization: M1 phenotypic microglia aggravates cerebral I/R injury, whereas the M2 phenotype supports neuroprotection and tissue repair. Consequently, shifting microglial polarization toward the M2 phenotype has emerged as a promising strategy to reduce early ischemic damage. Additionally, energy failure during ischemia leads to excessive generation of reactive oxygen species (ROS), causing oxidative stress, a key mechanism underlying cerebral I/R injury. Oxidative stress is strongly linked to M1 microglial activation, which further amplifies ROS production. In contrast, suppressing oxidative stress can promote the polarization of microglia toward the M2 phenotype, which is characterized by enhanced antioxidant capacity. Nuclear factor erythroid 2-related factor 2 (Nrf2), a central transcriptional regulator of antioxidant defense, coordinates multiple signaling pathways that concurrently alleviate oxidative stress and encourage M2 microglial polarization. Hence, Nrf2 acts as a crucial mediator in the interplay between oxidative stress and M1/M2 microglial polarization. This review outlines the current understanding of oxidative stress and microglial polarization in cerebral I/R injury, highlights the central role of Nrf2 in regulating their crosstalk, and suggests novel therapeutic approaches to mitigate cerebral I/R injury.
PMID:42295478 | DOI:10.1007/s12035-026-05999-2