Scholarlink

<p>Whereas mitochondrial dysfunction is implicated in metabolic dysfunction-associated steatohepatitis (MASH), the precise underlying mechanisms remain obscure. Here, we identify the Sirtuin 3 (SIRT3)-Disulfide-bond-A oxidoreductase-like protein (DsbA-L)-Mitochondrial Transcription Factor A (TFAM) axis as a crucial suppressor for mitochondrial stress-induced cyclic GMP-AMP synthase (cGAS) activation in hepatocytes, thereby alleviating MASH in mice. SIRT3 facilitates the deacetylation of DsbA-L at lysine residues (Lys<sup>165</sup>, Lys<sup>167</sup>, and Lys<sup>177</sup>), which promotes the interaction between DsbA-L and TFAM, essential for the preservation of mitochondrial integrity and function. Hepatocyte-specific knockout of SIRT3 or DsbA-L in male mice promoted mitochondrial DNA release into the cytosol, resulting in activation of the cGAS pathway and exacerbation of MASH characteristics. Conversely, hepatocyte-specific knockout of cGAS or overexpression of DsbA-L mitigated diet- and SIRT3 deficiency-induced MASH progression. Our study underscores the clinical significance of targeting SIRT3 and cGAS as pivotal therapeutic avenues to inhibit the progression of MASH.</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

The SIRT3-DsbA-L-TFAM axis restrains cGAS-driven metabolic dysfunction-associated steatohepatitis in male mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月5日

查看全文
  • Li Hu,
  • Juli Bai,
  • Jie Wen,
  • Hairong Luo,
  • Dongqing Yin,
  • Bulent T. Delibasi,
  • Juanhong Liu,
  • Yan Yang,
  • Jingjing Zhang,
  • Cynthia Ju,
  • Alan Frazer,
  • Lily Q. Dong,
  • Feng Liu

摘要

Whereas mitochondrial dysfunction is implicated in metabolic dysfunction-associated steatohepatitis (MASH), the precise underlying mechanisms remain obscure. Here, we identify the Sirtuin 3 (SIRT3)-Disulfide-bond-A oxidoreductase-like protein (DsbA-L)-Mitochondrial Transcription Factor A (TFAM) axis as a crucial suppressor for mitochondrial stress-induced cyclic GMP-AMP synthase (cGAS) activation in hepatocytes, thereby alleviating MASH in mice. SIRT3 facilitates the deacetylation of DsbA-L at lysine residues (Lys165, Lys167, and Lys177), which promotes the interaction between DsbA-L and TFAM, essential for the preservation of mitochondrial integrity and function. Hepatocyte-specific knockout of SIRT3 or DsbA-L in male mice promoted mitochondrial DNA release into the cytosol, resulting in activation of the cGAS pathway and exacerbation of MASH characteristics. Conversely, hepatocyte-specific knockout of cGAS or overexpression of DsbA-L mitigated diet- and SIRT3 deficiency-induced MASH progression. Our study underscores the clinical significance of targeting SIRT3 and cGAS as pivotal therapeutic avenues to inhibit the progression of MASH.