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

Qianrang Lu1,2, Meiching Ong1,2, Xuewen Yi1,2

  • 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 19, 2025
PubMed

Insights

Coagulation Factor XIII-A (F13A1)-positive macrophages drive inflammation in metabolic-associated steatohepatitis (MASH). Targeting the F13A1/PKM2/HIF1A pathway offers a novel therapeutic strategy for MASH.

Area of Science:

  • Hepatology
  • Immunology
  • Molecular Biology

Background:

  • Macrophages are key players in liver inflammation and fibrosis in MASH.
  • Mechanisms of macrophage activation in MASH are not fully understood.

Purpose of the Study:

  • Identify the predominant macrophage subset in MASH livers.
  • Elucidate the molecular mechanisms driving MASH-associated macrophage activation.
  • Investigate F13A1 as a potential therapeutic target.

Main Methods:

  • Single-nucleus transcriptomic analysis of human MASH livers.
  • Validation in patient samples and murine models.
  • In vivo gene silencing and pharmacologic interventions.
  • Biochemical assays to study protein interactions and metabolic reprogramming.

Main Results:

  • F13A1-positive macrophages are the predominant subset in MASH livers.
  • Lipid-stressed hepatocytes induce F13A1 via S1P signaling.
  • F13A1 silencing reduces inflammation and liver injury.
  • F13A1 interacts with PKM2, promoting dimerization and IL1B upregulation via the PKM2/HIF1A axis.
  • F13A1 enhances the Warburg effect in macrophages.
  • PKM2 activation with DASA-58 inhibits F13A1-driven inflammation.

Conclusions:

  • F13A1 is a critical driver of macrophage-mediated inflammation in MASH.
  • The F13A1/PKM2/HIF1A pathway is a promising therapeutic target for MASH.
  • Pharmacologic targeting of PKM2 demonstrates therapeutic potential.
Keywords:
HIF1AMASHPKM2factor XIIImacrophage activation

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