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Mol. Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Macrophage-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fibrin 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 TNF\u03b1 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 PPAR\u03b1, thereby sterically hindering the access of USP53, which functions as a deubiquitinase, to PPAR\u03b1. This displacement prevented USP53-mediated deubiquitination, resulting in increased PPAR\u03b1 ubiquitination and proteasomal degradation, ultimately leading to suppression of fatty acid \u03b2-oxidation. Macrophage-specific FABP4 knockdown mirrored the therapeutic effects of soft fibrin, ameliorating MASH pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal that soft fibrin matrices promote anti-inflammatory macrophage polarization and mitigate MASH by enhancing fatty acid \u03b2-oxidation via downregulation of FABP4 and stabilization of PPAR\u03b1. Targeting the Fibrin-FABP4-PPAR\u03b1 axis may offer a novel therapeutic strategy for MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00018-026-06266-2","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T11:05:02Z","timestamp":1780571102000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Soft fibrin matrix instructs macrophage M2 polarization via FABP4-mediated enhancement of fatty acid \u03b2-oxidation to alleviate MASH"],"prefix":"10.1007","volume":"83","author":[{"given":"Ranran","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqing","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoran","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqingyuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0958-5506","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"issue":"10290","key":"6266_CR1","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","volume":"5","author":"EE Powell","year":"2021","unstructured":"Powell EE, Wong VW, Rinella M (2021) Non-alcoholic fatty liver disease. 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