{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:03:07Z","timestamp":1790708587329,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Asialoglycoprotein receptor 1 (ASGR1), a hepatocyte\u2010specific receptor, represents a potential therapeutic target for hypercholesterolemia. However, liver safety risks of ASGR1\u2010targeted therapies remain poorly characterized. This study aims to investigate the impact of ASGR1 deficency on liver fibrosis and its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      ASGR1 knockout (ASGR1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) mice and wild\u2010type controls were subjected to carbon tetrachloride (CCl\n                      <jats:sub>4<\/jats:sub>\n                      ) administration or bile duct ligation (BDL) to induce liver fibrosis. Serum biomarkers, including alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were measured. Transcriptomic analysis was performed to identify altered pathways. Primary mouse hepatocytes, HepG2 cells, and hepatic stellate cells (HSCs) were used for in vitro mechanistic validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ASGR1 deficiency significantly exacerbates liver fibrosis in both CCl\n                      <jats:sub>4<\/jats:sub>\n                      \u2010 and BDL \u2010induced models and specifically induces an increase in serum alkaline phosphatase (ALP), which showed greater sensitivity than alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Mechanistic studies showed that ASGR1 loss led to a significant increase in the transcription and secretion of hepatic ALP. Transcriptomic analysis revealed that ASGR1 knockout mice not only disrupted bile acid metabolism but also upregulated the synthesis of arachidonic acid metabolites (e.g., PTGES, a key enzyme involved in pro\u2010inflammatory eicosanoid synthesis) and the pro\u2010fibrotic factor TGF\u03b21, collectively accelerating fibrosis. Importantly, Supernatants from ASGR1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      primary mouse hepatocytes and HepG2 cells, as well as exogenous ALP, directly activated hepatic stellate cells (HSCs), promoting their activation and \u03b1\u2010SMA expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ASGR1 deficiency aggravates liver fibrosis, which is likely mediated through the \u201cASGR1\u2010arachidonic acid\u2010ALP\u201d axis that enhances pro\u2010inflammatory eicosanoid production and ALP secretion. These findings highlight the liver\u2010specific safety risk of ASGR1 as a therapeutic target for lipid disorders and provide mechanistic and translational references for clinical safety monitoring of ASGR1\u2010targeted drugs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/iid3.70496","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:09:13Z","timestamp":1787213353000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ASGR1 Deficiency Promotes Liver Fibrosis by Enhancing Pro\u2010Inflammatory Arachidonic Acid Metabolism and ALP Secretion"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8562-8013","authenticated-orcid":false,"given":"Hui","family":"Zhu","sequence":"first","affiliation":[{"name":"Clinical Biobank, National Infrastructures for Translational Medicine, Institute of Clinical Medicine Peking Union Medical College 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