Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis
- Xiao-Chen Xie
- Yang Guo
- Ran Guo
- Yong-Ze Li
- Shan-Shan Wang
- Xiao-You Jiang
- Shuang Hao
- Ye Zhang
- Yu-Han Li
- Xi-Yan Liu
- Xiao-Xu Wu
- Xin-Yue Zhang
- Wen-Dong Guo
- Yan-Ling Feng
- Jia-Bin Li
- Chen Liu
- Liang Wang
- Zhen-Hua Li
- Wei-Ping Teng
- Zhong-Yan Shan
- Liu Cao
- Qi-Qiang Guo
2026-07-24
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.