ANXA1-FPR1 signaling in myeloid cells drives MASH by elevating S100A4/A11

  • JHEP Rep. 2026 Apr 24;8(8):101869. doi: 10.1016/j.jhepr.2026.101869.
Siting Yang  1 ,  Shengying Qian  2 ,  Liu Yang  3 ,  Yanghuan He  4 ,  Shujun Ge  1 ,  Xinhuan Fu  5 ,  Siyue Dong  1 ,  Ru Ya  2 ,  Yingfen Chen  2 ,  Ningning Ma  6 ,  Peng Xiao  7 ,  Ziling Zhang  1 ,  Yue Zhou  2 ,  Yuanwen Chen  8 ,  Yan Wang  9 ,  Yong He  10
Affiliations
  • 1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 3. Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, China.
  • 4. Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China.
  • 5. Department of Infectious Diseases, Peking University First Hospital, Beijing, China.
  • 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • 7. Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China.
  • 8. Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 9. Department of Infectious Diseases, Peking University First Hospital, Beijing, China. Electronic address: [email protected].
  • 10. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address: [email protected].
PMID: 42035895 DOI: 10.1016/j.jhepr.2026.101869
Abstract

Background & aims: Inflammation plays a central role in the development of metabolic dysfunction-associated steatohepatitis (MASH). Formyl peptide receptor 1 (FPR1) in myeloid cells emerges as a crucial factor associated with the inflammatory response; however, whether and how FPR1 signaling affects MASH development remain largely unknown.

Methods: Neutrophil-specific Fpr1 knockout mice and macrophage-specific Fpr1 knockout mice were generated, and subjected to high-fat high-cholesterol (HFHC, n = 6-10) or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD, n = 5-9) feeding.

Results: After MASH diet feeding, both neutrophil and macrophage-specific Fpr1 knockout mice had lower inflammatory cell infiltration and less degree of liver fibrosis than control mice (p <0.05-0.001). Administration of a selective inhibitor of FPR1, Cyclosporin H, robustly ameliorated mouse MASH in vivo and the 3D NAC-organ human MASH model in vitro (reduction in fibrosis area by 50%, p <0.001). Mechanistically, transcriptomic analysis revealed that Fpr1 deficiency in myeloid cells limited inflammatory cell chemotaxis and migration, which were closely related with the downregulation of S100a4 and S100a11. Moreover, neutrophil-derived annexin A1 (ANXA1) activated FPR1 signaling in neutrophils and macro phages during MASH, resulting in upregulation of pro-inflammatory S100A4 and S100A11 (p <0.05-0.01). Importantly, hepatic and serum levels of ANXA1, S100A4, and S100A11 were significantly elevated in patients with MASH (n = 15 for serum samples or 20 for liver samples), which positively correlated with the hepatic levels of several pro-inflammatory genes and fibrogenic genes (p <0.05).

Conclusions: The ANXA1-FPR1 axis in myeloid cells worsens MASH by elevating S100A4 and S100A11 levels, suggesting that pharmacological inhibition of FPR1 signaling is a promising strategy to ameliorate MASH.

Impact and implications: FPR1 in myeloid cells is a crucial factor associated with the inflammatory response; however, whether FPR1 signaling affects MASH development remains largely unknown. In this study, we demonstrated that Fpr1 deficiency in myeloid cells and administration of an FPR1 inhibitor robustly limit MASH-related fibrosis, which is closely related with the downregulation of pro-inflammatory S100A4 and S100A11. In addition, neutrophil-derived ANXA1 elevates the expression of S100A4 and S100A11 in neutrophils and macrophages by activating FPR1 signaling, suggesting that the ANXA1-FPR1-S100A4/A11 axis plays an important role in worsening MASH.

Keywords
Inflammation; Liver fibrosis; MASLD; Macrophages; Neutrophils.
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