Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis

  • Sci Bull (Beijing). 2026 May 15;71(9):2283-2299. doi: 10.1016/j.scib.2026.04.016.
Mengya Geng  1 ,  Fanzheng Meng  2 ,  Hairui Li  2 ,  Lijie Sun  3 ,  Xuedan Sun  2 ,  Yu Ding  3 ,  Rongdongqing Shi  3 ,  Zhihua Wang  3 ,  Yabin Huang  2 ,  Jizhou Wang  2 ,  Yao Liu  2 ,  Jiabei Wang  2 ,  Peter J Little  4 ,  Suowen Xu  3 ,  Lianxin Liu  5 ,  Jianping Weng  6 ,  Sihui Luo  7
Affiliations
  • 1. Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; School of Clinical Medicine, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei 230001, China.
  • 2. Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 3. Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei 230001, China.
  • 4. School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba QLD 4102, Australia.
  • 5. Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: [email protected].
  • 6. Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei 230001, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 7. Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei 230001, China. Electronic address: [email protected].
PMID: 41997855 DOI: 10.1016/j.scib.2026.04.016
Abstract

The mechanisms underlying metabolic remodeling in metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. Targeting the process of de novo lipogenesis (DNL) in the liver has the potential to mitigate MASLD. Here we show that interferon-related developmental regulator 1 (IFRD1) expression negatively correlates with MASLD/metabolic-associated steatohepatitis (MASH) progression in human liver tissues. In multiple mouse models, Ifrd1-/- mice exhibit an exacerbated MASLD phenotype, while hepatocyte-specific IFRD1 expression suppresses MASH progression. Mechanistically, IFRD1 promotes GLUD1's mitochondrial localization via direct interaction, stabilizing the enzyme's activity to enhance α-ketoglutarate (α-KG) production. α-KG reduces H3K36me3 level at lipogenic genes, thereby inhibiting DNL and ameliorating MASH. α-KG supplementation reverses MASH exacerbation in Ifrd1-CKO mice. Collectively, our research establishes the IFRD1-GLUD1-α-KG axis as a critical metabolic-epigenetic regulatory hub, providing novel targets for inhibiting hepatic DNL and developing therapeutic agents for MASLD/MASH.

Keywords
Glutamate dehydrogenase 1; H3K36me3; Interferon-related developmental regulator 1; Mitochondria.
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