Synergistic regulation of neuroinflammation by mitophagy and the cGAS–STING pathway following ischemic stroke

Neuroinflammation is widely recognized as a major driver of secondary brain injury following ischemic stroke. Recent studies have shown that mitochondrial dysfunction-induced mitochondrial DNA (mtDNA) release is one of the key mechanisms activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mitophagy, as a quality control mechanism maintaining mitochondrial homeostasis, selectively clears damaged mitochondria, thereby limiting the leakage of abnormal mtDNA. Although previous reviews have outlined the general framework of the mitophagy-cGAS-STING interaction in neuroinflammation, this review places it within the specific context of ischemic stroke. It integrates the cell type-specificity of the neurovascular unit, explores both synergistic and interactive aspects, and evaluates targeted nanotherapeutic strategies. This article aims to explore the potential synergistic role of mitophagy and the cGAS-STING pathway in the pathological progression of ischemic stroke. First, the article elaborates on mitophagy and mitophagy-dependent regulation of neuroinflammation, highlighting its role in suppressing cGAS-STING activation by preventing mtDNA leakage. Second, it examines the cGAS-STING signaling pathway in neuroinflammation, with particular attention to cGAS-STING activation across neurovascular unit cell types (microglia, neurons, astrocytes, endothelial cells). Third, the functional synergy and potential molecular crosstalk between mitophagy and the cGAS–STING pathway in neuroinflammation are discussed. Finally, the article summarizes the potential therapeutic strategies targeting mitophagy and the cGAS-STING pathway, and further explores the emerging potential of microenvironment-responsive intelligent nanoplatforms to enhance drug delivery efficiency and multidimensional synergistic mechanisms by targeting the cGAS-STING pathway and mitochondria, thereby achieving precise immune regulation and improving therapeutic efficacy. This paper provides a mechanistic perspective on immune intervention for ischemic stroke and lays a theoretical foundation for future clinical translation strategies.