{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:52:48Z","timestamp":1793641968397,"version":"4.5.1"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute liver failure (ALF) is a life\u2010threatening condition that occurs when the liver sustains severe damage and rapidly loses its function. The primary cause of ALF is the overdose of acetaminophen (APAP), and its treatment is relatively limited. The involvement of the complement system in the development of ALF has been implicated. However, the related mechanisms remain poorly understood. Complement 3 (\n                    <jats:italic>C3<\/jats:italic>\n                    ) knockout mice, complement 3a receptor (C3aR) knockout mice, platelet C\u2010type lectin\u2010like receptor 2 (\n                    <jats:italic>Clec\u20102<\/jats:italic>\n                    )\u2013deficient mice, and myeloid cell podoplanin (\n                    <jats:italic>Pdpn<\/jats:italic>\n                    )\u2010deficient mice were generated. Liver tissues were collected for histological analysis, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. Our data demonstrated that APAP activated the C3\/C3aR pathway, leading to intrahepatic hemorrhage, ultimately resulting in hepatocyte necrosis. Deletion of C3 or C3aR mitigated APAP\u2010induced liver injury (AILI). C3\/C3aR signaling upregulated the expression and phosphorylation of transcription factors STAT3 and c\u2010Fos in hepatic Kupffer cells, which in turn increased PDPN expression, promoting platelet recruitment to the Kupffer cells via the interaction of PDPN and the CLEC\u20102 on platelets. Since the activation of platelets mediated by C3\/C3aR occurs irrespective of the major hemostatic pathways, blocking the C3\/C3aR pathway in ALF could be a coagulopathy\u2010sparing and novel therapeutic approach. In summary, this study unveiled the critical roles of the C3\/C3aR pathway in developing AILI, providing evidence that the C3\/C3aR pathway could be an effective therapeutic target for AILI.\n                  <\/jats:p>","DOI":"10.1096\/fj.202402278rr","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T09:30:34Z","timestamp":1736242234000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The\n                    <scp>C3<\/scp>\n                    \/\n                    <scp>C3aR<\/scp>\n                    pathway exacerbates acetaminophen\u2010induced mouse liver injury via upregulating podoplanin on the macrophage"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5047-7737","authenticated-orcid":false,"given":"Zhanli","family":"Xie","sequence":"first","affiliation":[{"name":"Jiangsu Institute of Hematology, National Clinical Research Center 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