Therapeutic targeting the cGAS-STING pathway associated with protein and gene: An emerging and promising novel strategy for aging-related neurodegenerative disease.

Neurodegenerative diseases (NDDs) represent a rapidly escalating global health challenge, contributing significantly to the worldwide disease burden and posing substantial threats to public health systems across nations. Among the many risk factors for neurodegeneration, aging is the major risk factor. In the context of aging, multiple factors lead to the release of endogenous DNA (especially mitochondrial DNA, mtDNA), which is an important trigger for the activation of the cGAS-STING innate immune pathway. Recent studies have identified an increasing role for activation of the cGAS-STING signaling pathway as a driver of senescence-associated secretory phenotypes (SASPs) in aging and NDDs. The cGAS-STING pathway mediates the immune sensing of DNA and is a key driver of chronic inflammation and functional decline during the aging process. Blocking cGAS-STING signaling may reduce the inflammatory response by preventing mtDNA release and enhancing mitophagy. Targeted inhibition of the cGAS-STING pathway by biological macromolecules such as natural products shows promise in therapeutic strategies for age-related NDDs. This review aims to systematically and comprehensively introduces the role of the cGAS-STING pathway in age-related NDDs in the context of aging while revealing the molecular mechanisms of the cGAS-STING pathway and its downstream signaling pathways and to develop more targeted and effective therapeutic strategies for NDDs.