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The role of the nuclear receptor constitutive androstane receptor (CAR) in endotoxin\u2010induced liver injury remains unclear. Here, this study reports that CAR is highly expressed in human and murine macrophages. CAR activation markedly attenuated endotoxin\u2010induced liver damage, alleviating hepatocyte death and hepatic inflammation. Macrophage\u2010hepatocyte coculture confirmed that CAR inhibited inflammation through macrophage crosstalk. CAR\u2010mediated hepatoprotection and anti\u2010inflammatory effects are absent in AAV8\u2010\n                    <jats:italic>F4\/80\u2010<\/jats:italic>\n                    sh\n                    <jats:italic>Car<\/jats:italic>\n                    \u2010treated mice, confirming the essential role of CAR in macrophages. Mechanistically, CAR is found to interact with\n                    <jats:italic>Tlr4<\/jats:italic>\n                    , and the suppressive effects of CAR on TLR4 are proven in\n                    <jats:italic>Tlr4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Furthermore, CAR activation reduced LPS\u2010induced inflammation in hMDMs, BMDMs, RAW264.7, and THP\u20101 cells, and\n                    <jats:italic>Car<\/jats:italic>\n                    or\n                    <jats:italic>Tlr4<\/jats:italic>\n                    knockdown abolished CAR\u2010mediated immunosuppression. Overall, these findings showed that macrophage CAR activation attenuated endotoxin\u2010induced liver injury and hepatic inflammation through the TLR4 signaling pathway, providing insights for treating inflammatory liver diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202506725","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T09:01:57Z","timestamp":1755507717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Constitutive Androstane Receptor in Macrophages Regulates Toll\u2010Like Receptor 4\u2010Mediated Innate Immune Responses Against Endotoxemic Liver Injury"],"prefix":"10.1002","volume":"12","author":[{"given":"Renjie","family":"Cao","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical Sciences Sun Yat\u2010Sen University Institute of Clinical Pharmacology Sun Yat\u2010Sen 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