Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis
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.
Authors
- Hairui Li (ORCID: https://orcid.org/0000-0002-8170-8013)
- Zhihua Wang (ORCID: https://orcid.org/0000-0001-8976-3212)
- Ya Ding (ORCID: https://orcid.org/0000-0001-6214-5641)
- Xuedan Sun (ORCID: https://orcid.org/0000-0003-4707-9230)
- Peter J. Little (ORCID: https://orcid.org/0000-0003-3726-9153)
- Mengya Geng
- Fanzheng Meng
- Lijie Sun
- Shuai Xu (ORCID: https://orcid.org/0000-0001-9928-5437)
- Rong Shi (ORCID: https://orcid.org/0000-0001-6057-2439)
- Yabin Huang
- Jiabei Wang
- Jizhou Wang
- Lianxin Liu
- Yao Liu
- Jianping Weng
Institutions
- University of Science and Technology of China (CN)
- The University of Queensland (AU)
- Anhui Medical University (CN)
Publication Details
- Journal
- Science Bulletin
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1016/j.scib.2026.04.016
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- University of Science and Technology of China
- Anhui Provincial Department of Education