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In this study, we examined the effects of chronic alcohol intake on APAP\u2010induced liver injury in mice. Our results indicated that subchronic alcohol exposure significantly increased the mortality rate in APAP\u2010overdosed mice. Alcohol pretreatment also exacerbated APAP\u2010induced hepatic damage, as evidenced by elevated serum ALT and AST levels, enhanced inflammatory responses, and aggravated oxidative stress. Quantitative polymerase chain reaction (qPCR) analysis revealed that alcohol consumption suppressed mitochondrial biogenesis (MB)\u2010related genes, including\n                    <jats:italic>Pgc-1\u03b1<\/jats:italic>\n                    and transcription factor A, mitochondrial (\n                    <jats:italic>TFAM<\/jats:italic>\n                    ). Notably, macrophage depletion via clodronate liposomes not only attenuated hepatocyte injury and inflammation induction but also restored the expression of MB\/function\u2010related genes, including\n                    <jats:italic>Pgc-1\u03b1<\/jats:italic>\n                    ,\n                    <jats:italic>TFAM<\/jats:italic>\n                    , and\n                    <jats:italic>Opa1<\/jats:italic>\n                    . These findings suggest macrophage\u2010involved inflammatory amplification may aggravate APAP\u2010induced liver injury, at least in part, by impairing mitochondrial adaptive repair responses.\n                  <\/jats:p>","DOI":"10.1155\/mi\/4167398","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T09:21:09Z","timestamp":1786958469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Subchronic Alcohol Exposure Exacerbates Acetaminophen\u2010Induced Acute Liver Injury via Macrophage\u2010Mediated Inflammation and Mitochondrial Dysfunction"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2521-5245","authenticated-orcid":false,"given":"Qingyang","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weigao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiling","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuening","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadierya","family":"Kuerban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingna","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3721-198X","authenticated-orcid":false,"given":"Fei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2071-6307","authenticated-orcid":false,"given":"Na","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao","family":"Da","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8078-6864","authenticated-orcid":false,"given":"Dan","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"e_1_2_10_1_2","unstructured":"World Health Organization Alcohol. 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