Abstract

Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.