Recently, the research team led by Professors Jianping Weng, Sihui Luo and Lianxin Liu from the University of Science and Technology of China published a study titled Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis in Science Bulletin .
By analyzing clinical specimens and conducting experiments with multiple mouse models, this study yielded three pivotal innovative findings: First, it defined the disease-protective function of IFRD1. The research team verified that the expression level of IFRD1 in human liver tissue exhibits a significant negative correlation with the progression of metabolic dysfunction-associated fatty liver disease (MASLD). Knockout of this factor exacerbates pathological phenotypes of MASLD in mice, whereas hepatocyte-specific overexpression effectively halts disease deterioration. Second, it elucidated an unprecedented molecular regulatory mechanism. IFRD1 binds to specific amino acid residues of glutamate dehydrogenase 1 (GLUD1), facilitating its mitochondrial translocation and stabilizing its enzymatic activity, which consequently boosts the production of α-ketoglutarate (α-KG). Through epigenetic regulation, α-KG reduces the methylation modification of lipogenic genes, thereby directly suppressing de novo hepatic lipogenesis. Third, it validated the translational potential of therapeutic interventions. Exogenous supplementation with α-KG effectively rescues the aggravated MASLD phenotype in IFRD1-knockout mice. More importantly, clinical specimen analyses confirmed that hepatic GLUD1 enzymatic activity and α-KG levels are markedly reduced in MASLD patients, accompanied by elevated methylation of relevant genes; these biomarkers are significantly negatively correlated with IFRD1 expression, proving that this regulatory axis also plays a critical role in the pathogenesis of human MASLD.
This research systematically delineates the IFRD1-GLUD1-α-KG axis as a core signaling cascade bridging metabolic regulation and epigenetic modification. For the first time, it establishes a clinical correlation between IFRD1 and MASLD progression, uncovers a novel mechanism by which GLUD1 enzymatic activity modulates MASLD, and verifies the epigenetic regulatory function of the metabolic intermediate α-KG. These findings pioneer a new paradigm for targeted therapy of MASLD centered on the "metabolism-epigenetics" regulatory network.
Science Bulletin
Experimental study