The SIRT3-DsbA-L-TFAM axis restrains cGAS-driven metabolic dysfunction-associated steatohepatitis in male mice
- 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
2026-05-04
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 165 , Lys 167 , and Lys 177 ), 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.