Rebalancing redox homeostasis: A pivotal regulator of the cGAS-STING pathway in autoimmune diseases

Abstract

Autoimmune diseases (ADs) arise from the breakdown of immune tolerance to self-antigens, leading to pathological tissue damage. Proinflammatory cytokine overproduction disrupts redox homeostasis across diverse cell populations, generating oxidative stress that induces DNA damage through multiple mechanisms. Oxidative stress-induced alterations in membrane permeability and DNA damage can lead to the recognition of double-stranded DNA (dsDNA), mitochondrial DNA (mtDNA) and micronuclei-DNA (MN-DNA) by DNA sensors, thereby initiating activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. While previous reviews have characterized cGAS-STING activation in autoimmunity, the reciprocal regulation between redox homeostasis and cGAS-STING activation remains insufficiently defined. This narrative review examines oxidative stress-mediated DNA damage as a critical driver of pathological cGAS-STING signaling and delineates molecular mechanisms linking redox homeostasis to autoimmune pathogenesis. Furthermore, we propose therapeutic strategies that combine redox restoration with the attenuation of aberrant cGAS-STING activation, thereby establishing a mechanistic foundation for precision interventions in autoimmune disorders.

Methods

The manuscript is formatted as a narrative review. We conducted a comprehensive search strategy using electronic databases such as PubMed, Google Scholar and Web of Science. Various keywords were used, such as "cGAS-STING," "Redox homeostasis," "Oxidative stress," "pentose phosphate pathway," "Ferroptosis," "mtDNA," "dsDNA," "DNA damage," "Micronuclei," "Reactive oxygen species," "Reactive nitrogen species," "Nanomaterial," "Autoimmune disease," "Systemic lupus erythematosus," "Type 1 diabetes," "Rheumatoid arthritis," "Multiple sclerosis," "Experimental autoimmune encephalomyelitis," "Psoriasis," etc. The titles and abstracts were reviewed for inclusion into this review. After removing duplicates and irrelevant studies, 174 articles met inclusion criteria (original research, English language).