中国科学技术大学附属第一医院骆斯慧小组的一项最新研究揭示了肝脏IFRD1通过GLUD1/α-KG轴抑制代谢功能障碍相关的脂肪肝疾病。相关论文于2026年4月6日发表在《科学通报》杂志上。

在这里，课题组发现干扰素相关发育调节因子1 （IFRD1）的表达与人肝组织中MASLD/代谢相关脂肪性肝炎（MASH）的进展呈负相关。在多小鼠模型中，Ifrd1-/-小鼠表现出加重的MASLD表型，而肝细胞特异性Ifrd1表达抑制MASH进展。在机制上，IFRD1通过直接相互作用促进GLUD1的线粒体定位，稳定酶的活性，促进α-酮戊二酸（α-KG）的产生。α-KG减少H3K36me3在脂肪生成基因上的占用，从而抑制DNL，改善MASH。α-KG补充可逆转Ifrd1-CKO小鼠的MASH恶化。总之，他们的研究确立了IFRD1-GLUD1-α-KG轴作为一个关键的代谢-表观遗传调控枢纽，为抑制肝脏DNL和开发MASLD/MASH治疗药物提供了新的靶点。

研究人员表示，代谢功能障碍相关脂肪变性肝病（MASLD）的代谢重塑机制尚不清楚。靶向肝脏中的新生脂肪生成（DNL）过程具有减轻MASLD的潜力。

附：英文原文

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

Author: Lianxin Liu c, Jianping Weng e f, Sihui Luo a

Issue&Volume: 2026/04/06

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 occupancy 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.

DOI: 10.1016/j.scib.2026.04.016

Source: https://www.sciencedirect.com/science/article/abs/pii/S2095927326003658