2. Academic Validation
  3. F13A1-Mediated Macrophage Activation Promotes MASH Progression via the PKM2/HIF1A Pathway

F13A1-Mediated Macrophage Activation Promotes MASH Progression via the PKM2/HIF1A Pathway

  • Adv Sci (Weinh). 2025 Dec 19:e18128. doi: 10.1002/advs.202518128.
Qianrang Lu 1 2,  Meiching Ong 1 2,  Xuewen Yi 1 2,  Muqiong Xing 3,  Xinyao Tian 4,  Ke Zhang 1 2,  Ling Lu 5 6,  Hao Wang 7,  Xiaohan Lin 1 2,  Jun Fang 1 2,  Aibo Mu 1 2,  Jiaying Cao 1 2,  Jingyu Jiang 1 2,  Feng Gao 1,  Hongjun Li 3 4 8 9,  Baohong Wang 10,  Qi Ling 1 2 10
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.
  • 3 State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Hepatobiliary Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 6 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
  • 7 Hepatobiliary Center, The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
  • 8 Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 9 Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
  • 10 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
PMID: 41417477 DOI: 10.1002/advs.202518128
Abstract

Macrophages are central mediators of hepatic inflammation and fibrosis in metabolic-associated steatohepatitis (MASH), yet the mechanisms driving their activation remain unclear. Integration of four human single-nucleus transcriptomic datasets identified Coagulation Factor XIII-A (F13A1)-positive macrophages as the predominant subset in MASH livers, a finding validated in patient samples and murine models. Lipid-stressed hepatocytes induce F13A1 expression through a sphingosine-1-phosphate (S1P)-dependent mechanism. Silencing F13A1 suppressed the pro-inflammatory phenotype and alleviated hepatic injury in vivo. Mechanistically, F13A1 directly interacted with Pyruvate Kinase M2 (PKM2), promoting its dimerization, a process enhanced by intracellular calcium levels. Dimerized PKM2 translocated into the nucleus and upregulates interleukin-1 beta (IL1B) expression via the PKM2/HIF1A (Hypoxia-inducible factor 1-alpha) axis. In addition, F13A1 enhanced the Warburg effect in macrophages through PKM2-mediated metabolic reprogramming. Pharmacologic activation of PKM2 with DASA-58 abrogated F13A1-driven inflammation, and PEG-PLA micelle-mediated delivery of DASA-58 ameliorated hepatic inflammation in vivo. These findings establish F13A1 as a critical driver of macrophage-mediated inflammation in MASH and highlight the F13A1/PKM2/HIF1A pathway as a promising therapeutic target.

Keywords

HIF1A; MASH; PKM2; factor XIII; macrophage activation.

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