2. Academic Validation
  3. Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1

Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1

  • Cell Rep. 2025 Mar 25;44(3):115426. doi: 10.1016/j.celrep.2025.115426.
Penghui Hu 1,  Xiao Shan 2,  Hongyuan Dong 3,  Sujun Yu 3,  Baochen Wang 3,  Hui Xiong 3,  Zemin Ji 3,  Weijia Jing 3,  Yan Cui 3,  Zihan Li 3,  Yanzhao Zhou 4,  Zhe Wang 2,  Jinrong Wang 3,  Jiuzhou Tang 3,  Ting Wang 5,  Keliang Xie 6,  Qiujing Yu 7
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 2 Department of Health Management Center and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, China.
  • 3 Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 4 Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450008, China.
  • 5 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin 300070, China.
  • 6 Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Anesthesiology, Tianjin Institute of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: xiekeliang2009@hotmail.com.
  • 7 Department of Health Management Center and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, China; Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: yuqiujing@uestc.edu.cn.
PMID: 40096087 DOI: 10.1016/j.celrep.2025.115426
Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive disease with only one approved treatment currently available. Hepatic phosphoglycerate dehydrogenase (PHGDH), the rate-limiting Enzyme of the serine biosynthesis pathway, regulates MAFLD development. However, the role of macrophage PHGDH in MAFLD progression remains unclear. Here, we demonstrate that the lipotoxicity inducer palmitic acid (PA) significantly increases macrophage PHGDH expression and that PHGDH deficiency in macrophages promotes PA-induced inflammatory responses. Myeloid-specific PHGDH deficiency exacerbates MAFLD in mice. Mechanistically, tetrameric PHGDH binds to transforming growth factor-β-activated kinase 1 (TAK1) to inhibit its interaction with TAK1 binding protein 1 (TAB1), sequentially suppressing the activation of TAK1 and downstream NF-κB and MAPK signaling. Inhibition of TAK1 activation slows the development of metabolic dysfunction-associated steatohepatitis (MASH) caused by myeloid PHGDH knockout. Importantly, adeno-associated virus-mediated PHGDH overexpression in liver macrophages alleviates MAFLD in mice. Collectively, these results identify macrophage PHGDH as a promising therapeutic agent for MAFLD.

Keywords

CP: Immunology; CP: Metabolism; macrophage; metabolic dysfunction-associated fatty liver disease; phosphoglycerate dehydrogenase; transforming growth factor-β-activated kinase 1.

Figures
Products