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

## TL;DR

This study identifies F13A1 as a key driver of macrophage activation in fatty liver disease, revealing a new pathway for potential treatment.

## Contribution

The study discovers the F13A1/PKM2/HIF1A pathway as a novel mechanism in MASH progression.

## Key findings

- F13A1-positive macrophages are predominant in MASH livers and promote inflammation.
- F13A1 interacts with PKM2, enhancing its dimerization and nuclear translocation.
- Pharmacologic targeting of PKM2 reduces F13A1-driven inflammation in vivo.

## 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.

In fatty liver disease, hepatocytes exposed to palmitate release S1P, which activates calcium signaling in macrophages. Elevated calcium enhances the activity of F13A1, driving PKM2 dimerization. The PKM2 dimers cause Warburg effect, translocate to the nucleus, cooperate with HIF1A, and upregulate IL1B expression, ultimately promoting classical activation of macrophages and contributing to hepatic inflammation.