The cGAS-STING signaling pathway: A central regulator and novel therapeutic target in skeletal muscle pathophysiology.

Abstract

The cGAS-STING signaling pathway is a central component of the innate immune system. Skeletal muscle, the body's largest metabolic and endocrine organ, is essential for overall health, and maintaining its homeostasis is critically important. This review systematically elaborates on the central position and "double-edged sword" role of the cGAS-STING pathway in skeletal muscle pathophysiology. We detail how, under various pathological stimuli-such as metabolic stress, physical injury, aging, toxin exposure, and systemic diseases-cytoplasmic DNA accumulation aberrantly activates the cGAS-STING pathway. Excessive activation of this pathway drives chronic inflammation, metabolic disturbances, and induces various forms of programmed cell death and cellular senescence. These effects collectively lead to muscle atrophy, fibrosis, and impaired regeneration. Conversely, during physiological adaptation like exercise training, moderate activation of this pathway can facilitate beneficial metabolic remodeling and muscle fiber type transformation. This article critically assesses current research challenges and limitations, particularly regarding cell specificity, the distinction between physiological and pathological activation, disease heterogeneity, and model systems. It also explores potential therapeutic strategies, supported by molecular docking analyses that predict high-affinity interactions between key inhibitors and cGAS/STING proteins. These include small-molecule inhibitors, intervention with upstream activating signals, lifestyle management, and novel biologics with targeted delivery systems. Ultimately, we emphasize that a deeper understanding and precise modulation of cGAS-STING signaling will open new perspectives and offer a promising translational medicine outlook for preventing and treating a range of refractory muscle diseases.