The role of mitophagy in regulating the cGAS–STING signaling pathway in central nervous system diseases

Mitophagy is a selective autophagic process responsible for the clearance of superfluous or dysfunctional mitochondria, playing a vital role in maintaining mitochondrial homeostasis and cellular stability. Impaired mitophagy can lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, where it is detected by the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. This activation triggers innate immune responses and inflammatory cascades, contributing to the pathogenesis of various diseases. This review summarizes the current understanding of how mitophagy regulates the cGAS–STING signaling pathway in central nervous system (CNS) diseases, with a focus on Parkinson’s disease (PD), parkinsonism, Alzheimer’s disease (AD), aging, ataxia telangiectasia (A-T), postoperative cognitive dysfunction (POCD), early brain injury (EBI) following subarachnoid hemorrhage (SAH), sepsis-associated encephalopathy (SAE), hypoxic-ischemic encephalopathy (HIE), and hypothalamic inflammation. Additionally, potential therapeutic strategies targeting mitophagy or the cGAS–STING signaling pathway are discussed, offering new insights for the prevention and treatment of CNS diseases. By modulating the cGAS–STING signaling pathway, mitophagy plays a critical role in the pathogenesis of CNS diseases, positioning it as a promising therapeutic target.