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Punicalagin (PUN), a polyphenolic compound derived from pomegranate, has demonstrated hepatoprotective effects in preclinical models; however, its molecular mechanisms underlying macrophage polarization and inflammatory signaling remain unclear. This study aims to investigate the role of PUN in modulating macrophage polarization and inflammatory pathways in chemical\u2010 and drug\u2010induced ALI. CCL\n                    <jats:sub>4<\/jats:sub>\n                    \u2010 and APAP\u2010induced ALI mouse models were employed to assess the hepatoprotective effects of PUN through liver enzyme analysis, histology, and immune phenotyping. In\u00a0vitro, LPS\u2010stimulated RAW264.7 macrophages were treated with PUN, and mechanisms were examined through western blotting, qRT\u2010PCR, flow cytometry, and ELISA. PUN (12.5\u2009mg\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) significantly reduced serum levels of ALT and AST, as well as the necrotic area in both ALI models. It reduced hepatic infiltration of monocyte\u2010derived macrophages (MDMs) and lowered the expression of M1 markers (CD86, iNOS), while simultaneously increasing the expression of M2 markers (CD206, Arg\u20101). Mechanistically, PUN inhibited the phosphorylation of NF\u2010\u03baB and STAT1, while promoting the activation of STAT3, which resulted in a reduction of TNF\u2010\u03b1 and IL\u20106 levels (approximately 62%\u201371%), alongside an increase in IL\u201010 and TGF\u2010\u03b2, both in\u00a0vivo and in\u00a0vitro. Similar reprogramming from M1 to M2 and cytokine shifts were observed in LPS\u2010challenged RAW264.7 cells. PUN alleviates ALI by promoting M1\u2010to\u2010M2 macrophage polarization through the dual inhibition of NF\u2010\u03baB\/STAT1 and the activation of STAT3. These findings underscore PUN as a potential therapeutic agent for ALI by reprogramming the hepatic immune microenvironment.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70228","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T08:18:18Z","timestamp":1769156298000},"page":"1318-1333","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Punicalagin Alleviates Acute Liver Injury via Dual\n                    <scp>STAT1<\/scp>\n                    \/\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Inhibition and\n                    <scp>STAT3<\/scp>\n                    Activation to Orchestrate M1\u2010to\u2010M2 Macrophage Polarization"],"prefix":"10.1002","volume":"40","author":[{"given":"Yixuan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Fujian Institute of Digestive Disease Fujian Medical University Union Hospital  Fuzhou China"},{"name":"The Clinical Laboratory Center The Second Affiliated Hospital of Fujian Medical University  Quanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition Fujian Medical University Union Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhen","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Provincial Center for Clinical Laboratory Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenglin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Fujian Institute of Digestive Disease Fujian Medical University Union Hospital  Fuzhou China"},{"name":"Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Fujian Institute of Digestive Disease Fujian Medical University Union Hospital  Fuzhou China"},{"name":"Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7134-719X","authenticated-orcid":false,"given":"Yuehong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Fujian Institute of Digestive Disease Fujian Medical University Union Hospital  Fuzhou China"},{"name":"Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases  Fuzhou 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