ArticleCellular and molecular life sciences : CMLS2026
Soft fibrin matrix instructs macrophage M2 polarization via FABP4-mediated enhancement of fatty acid β-oxidation to alleviate MASH.
Article in Cellular and molecular life sciences : CMLS, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMacrophage-driven inflammation is a key pathogenic factor in metabolic dysfunction-associated steatohepatitis (MASH). While fibrin deposition is observed in MASH livers, its role in regulating macrophage polarization and disease progression remains unclear.
methodsWe investigated fibrin deposition in liver tissues from MASH patients and high-fat diet (HFD)-induced MASH mice. Macrophages were cultured in soft or stiff 3D fibrin matrices to assess polarization phenotypes. In vivo, macrophages pre-cultured in soft or stiff fibrin were adoptively transferred into HFD-fed mice. Mechanistic studies involved siRNA-mediated knockdown, overexpression, chromatin immunoprecipitation, co-immunoprecipitation, and metabolomic analyses. Macrophage-specific FABP4 knockdown was achieved using an AAV8 vector expressing F4/80-driven FABP4 shRNA and eGFP.
resultsFibrin deposition was significantly elevated in MASH livers and correlated with pro-inflammatory macrophage infiltration. Macrophages cultured in soft fibrin matrices exhibited enhanced anti-inflammatory (M2) polarization, characterized by increased Arg1 and CD206 and decreased iNOS and TNFα expression. Adoptive transfer of soft fibrin-cultured macrophages alleviated hepatic steatosis, insulin resistance, and oxidative stress in MASH mice. Mechanistically, soft fibrin downregulated FABP4 expression by inhibiting ITGB2/STAT1 signaling. FABP4 competitively bound to PPARα, thereby sterically hindering the access of USP53, which functions as a deubiquitinase, to PPARα. This displacement prevented USP53-mediated deubiquitination, resulting in increased PPARα ubiquitination and proteasomal degradation, ultimately leading to suppression of fatty acid β-oxidation. Macrophage-specific FABP4 knockdown mirrored the therapeutic effects of soft fibrin, ameliorating MASH pathology.
conclusionsOur findings reveal that soft fibrin matrices promote anti-inflammatory macrophage polarization and mitigate MASH by enhancing fatty acid β-oxidation via downregulation of FABP4 and stabilization of PPARα. Targeting the Fibrin-FABP4-PPARα axis may offer a novel therapeutic strategy for MASH.
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