Metabolic reprogramming and polarization of microglia in cerebral ischemia: the roles of mitochondria and inflammasomes

Abstract

Mitochondrial dysfunction, metabolic reprogramming, and NLRP3 inflammasome activation have been widely studied in post-ischemic microglia. However, a systems-level understanding of how these three processes interact as a spatiotemporal regulatory network is lacking. Furthermore, although most prior microglial research has relied on a traditional “binary differentiation model,” single-cell sequencing has since uncovered a diverse spectrum of microglial subtypes, expanding this framework. Additionally, key differences exist between humans and mice regarding the NLRP3 inflammasome and related pathways; thus, regulatory feedback mechanisms identified in mouse models must be interpreted with caution. This review outlines the polarization and metabolic features of post-ischemic microglia and examines how dysregulated mitochondrial quality control drives the release of mitochondrial ROS (mtROS), mtDNA, and cardiolipin. These factors, alongside succinate-mediated reverse electron transport and lactate accumulation, induce NLRP3 inflammasome assembly. Once the NLRP3 inflammasome is activated, caspase-1 cleaves gasdermin D (GSDMD), yielding the N-terminal fragment (GSDMD-NT), which directly perforates the inner and outer mitochondrial membranes, establishing a positive feedback loop: “mitochondrial damage → inflammasome activation → further mitochondrial damage.” Additionally, this review stratifies this axis into hyperacute, subacute, and chronic temporal phases and identifies key bottlenecks in advancing from target validation to clinical application An integrated “MQC-metabolism-inflammation” framework is proposed alongside two testable hypotheses and an analysis of current translational limitations. Future studies leveraging single-cell multi-omics to map subpopulation dynamics, metabolic flux analysis to quantify functional metabolite thresholds, and humanized models with bidirectional clinical.

The authors' abstract, as published at the source. Journal of Translational Medicine, 2026 · DOI ↗