2. Academic Validation
  3. Short-chain acyl-CoA dehydrogenase initiates mtDNA demethylation and leakage to fuel antitumor immunity in colorectal cancer

Short-chain acyl-CoA dehydrogenase initiates mtDNA demethylation and leakage to fuel antitumor immunity in colorectal cancer

  • Signal Transduct Target Ther. 2026 Mar 26;11(1):113. doi: 10.1038/s41392-026-02675-8.
Fang Yang # 1 2 3 4,  Meng Wang # 1 2 4,  Shaofan Hu # 1 2 4,  Xu Guan # 5 6,  Kun Zhao 1 4,  Yong Zhou 7,  Hui Yao 2 8,  Tianying Zhang 1 2 4,  Liuli Li 1 2 4,  Yuan Gao 1 4,  Sijie Zhao 1 4,  Nan Liu 1 4,  Weidong Xiao 9,  Yuancai Xiang 10,  Hongming Miao 11 12 13
Affiliations

Affiliations

  • 1 Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, China.
  • 2 Jinfeng Laboratory, Chongqing, China.
  • 3 Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China.
  • 4 Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Third Military Medical University (Army Medical University), Chongqing, China.
  • 5 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 6 Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Hospital Affiliated with Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated with Shanxi Medical University, Taiyuan, China.
  • 7 Chongqing Weisiteng Biotech Transnational Research Institute, Chongqing, China.
  • 8 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China.
  • 9 Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
  • 10 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China. [email protected].
  • 11 Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, China. [email protected].
  • 12 Jinfeng Laboratory, Chongqing, China. [email protected].
  • 13 Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Third Military Medical University (Army Medical University), Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 41888107 DOI: 10.1038/s41392-026-02675-8
Abstract

Reprogramming of lipid metabolism and cyclic GMP‒AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling is associated with Cancer development. However, whether and how fatty acid metabolism regulates the cGAS‒STING pathway in colorectal Cancer (CRC) remains to be elucidated. In this study, we found that short-chain acyl-CoA dehydrogenase (ACADS) is aberrantly deficient in CRC cells and is associated with Cancer progression in human patients. We further revealed that ablation of ACADS promoted CRC progression by orchestrating the cGAS‒STING signaling-dependent immunosuppressive tumor microenvironment (TME) in mouse xenografts and AOM/DSS-induced CRC models. Mechanistically, ACADS deficiency suppressed cGAS‒STING signaling by inhibiting mtDNA leakage in a nonmetabolic manner. ACADS binds to and inhibits mitochondrial DNMT1 (mito-DNMT1)-dependent mtDNA methylation, thereby stabilizing mtDNA and inhibiting its leakage. Genetic and pharmacological modulation of mito-DNMT1 restored ACADS-regulated mtDNA leakage, cGAS‒STING signaling, and CRC progression. Importantly, strong correlations between ACADS, mito-DNMT1, and STING signaling and the immune TME were found in patients with CRC. Furthermore, we screened and identified an old drug, hypericin, as an ACADS-binding compound that upregulates ACADS expression. Hypericin treatment can mimic ACADS overexpression-regulated pathways, ultimately improving the immune TME and suppressing CRC growth. These findings highlight a previously undiscovered ACADS/mito-DNMT1 complex that links fatty acid metabolism reprogramming to mtDNA methylation and cGAS‒STING signaling-dependent antitumor immunity.

Figures
Products
Inhibitors & Agonists
Other Products