JHEP reports : innovation in hepatology · 2026
ANXA1-FPR1 signaling in myeloid cells drives MASH by elevating S100A4/A11.
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Yang Siting, Qian Shengying, Yang Liu, He Yanghuan, Ge Shujun, Fu Xinhuan, Dong Siyue, Ya Ru, Chen Yingfen, Ma Ningning, Xiao Peng, Zhang Ziling, Zhou Yue, Chen Yuanwen, Wang Yan, He Yong
Аннотация
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.
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.