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Here, we report that PEAR1 expression and vascular permeability are increased in the lung tissues of septic mice.\n                    <jats:italic>Pear1<\/jats:italic>\n                    knockdown markedly reduces pulmonary vascular permeability and consequently attenuates lung injury in septic mice. Mechanistically, PEAR1 promotes the AARS1\u2010mediated lactylation of HIF\u20101\u03b1, primarily at lysine 172 (K172). This lactylation event, in turn, increases the affinity of HIF\u20101\u03b1 for importin \u03b1, thereby facilitating HIF\u20101\u03b1 nuclear translocation. Importantly, HIF\u20101\u03b1 K172 lactylation promotes glycolysis, and glycolysis\u2010derived lactate further drives H3K18 lactylation. In addition, this lactate\u2010dependent histone modification is enriched at the\n                    <jats:italic>Pear1<\/jats:italic>\n                    promoter, resulting in further increases in glycolysis and pulmonary vascular permeability. In vivo, both\n                    <jats:italic>Pear1<\/jats:italic>\n                    knockout and the targeted delivery of\n                    <jats:italic>Pear1<\/jats:italic>\n                    siRNA to inflammatory vascular endothelial cells using E\u2010selectin\u2010binding peptide\u2010modified liposomes ameliorate ALI, and improve survival in mice with polymicrobial sepsis. Our study identifies K172 as a previously unreported lactylation site on HIF\u20101\u03b1 and shows that PEAR1 promotes AARS1\u2010mediated HIF\u20101\u03b1 lactylation, enhances glycolysis, and increases H3K18la enrichment at the\n                    <jats:italic>Pear1<\/jats:italic>\n                    promoter, thereby forming a positive feedback loop.\n                  <\/jats:p>","DOI":"10.1002\/advs.76592","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:14:51Z","timestamp":1784024091000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PEAR1 Promotes Glucose Metabolism Reprogramming in Sepsis\u2010Associated Acute Lung Injury via AARS1\u2010Mediated HIF\u20101\u03b1 Lactylation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-6507","authenticated-orcid":false,"given":"Shuai","family":"Li","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongqing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit The First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit The First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care 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