Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月26日

查看全文
  • Fang Yang,
  • Meng Wang,
  • Shaofan Hu,
  • Xu Guan,
  • Kun Zhao,
  • Yong Zhou,
  • Hui Yao,
  • Tianying Zhang,
  • Liuli Li,
  • Yuan Gao,
  • Sijie Zhao,
  • Nan Liu,
  • Weidong Xiao,
  • Yuancai Xiang,
  • Hongming Miao

摘要

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.