cGAS-STING signaling pathway: a central pathological mechanism and emerging therapeutic target for postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication in older patients following surgery. However, the upstream molecular triggers of perioperative neuroinflammation, a key factor in its pathogenesis, remain insufficiently understood. This review systematically examines the emerging evidence implicating the cGAS-STING signaling pathway as a potentially central mediator in the pathological progression of POCD. Integrating recent advancements, we outline a critical pathological cascade in POCD: perioperative stressors, including anesthesia and surgical trauma, induce mitochondrial injury, resulting in the release of mitochondrial DNA (mtDNA) into the cytosol. This leaked mtDNA functions as an endogenous danger signal, activating the cGAS-STING pathway in brain microglia. Activation of this pathway drives neuroinflammation, characterized by proinflammatory (M1-like) microglial polarization, regulated cell death (e.g., pyroptosis), and a self-perpetuating cycle of mitochondrial dysfunction, ultimately leading to neuronal damage and cognitive decline. We propose the mtDNA-cGAS-STING axis as a candidate pivotal link between perioperative stress and the neuropathology of POCD, based on converging preclinical evidence. Therapeutic strategies targeting this pathway, such as cGAS-STING inhibition or the promotion of mitophagy, have shown significant neuroprotective effects in preclinical studies. These findings offer promising avenues for the prevention and treatment of POCD and highlight potential implications for perioperative neuroprotection in older adults.