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Dendritic cells (DCs) play a pivotal role in immune regulation; however, their exact contribution to ALI pathogenesis remains unclear. This study demonstrates that the upregulation of the glycolytic regulator 6\u2010phosphofructo\u20102\u2010kinase\/fructose\u20102,6\u2010bisphosphatase 2 (PFKFB2) by hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) enhances glycolysis, drives DC maturation, and exacerbates inflammation, contributing to the pathogenesis of ALI. The findings reveal that HIF\u20101\u03b1 directly binds to the PFKFB2 promoter and drives its transcription, leading to increased glycolysis, accelerated DC maturation, and amplified immune activation. In paraquat (PQ)\u2010ALI and lipopolysaccharide (LPS)\u2010ALI mouse models, DC\u2010specific PFKFB2 knockout and DC\u2010targeted delivery of HIF\u20101\u03b1 inhibitor\u2010loaded nanoparticles each significantly suppressed DC maturation and alleviated ALI severity. Analyses of lung tissues from patients with PQ poisoning, secondary bacterial pneumonia (2\u00b0BP), and Coronavirus Disease 2019 (COVID\u201019), as well as from normal controls, confirmed these findings, showing increased PFKFB2 expression and DC maturation during ALI. These findings highlight the HIF\u20101\u03b1\u2013PFKFB2 signaling pathway as a critical regulator of glycolysis\u2010driven DC maturation and immune activation, offering novel insights into immunometabolic regulation and a promising therapeutic target for ALI.<\/jats:p>","DOI":"10.1002\/advs.202502428","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:39:17Z","timestamp":1753875557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["PFKFB2\u2010Driven Glycolysis Promotes Dendritic Cell Maturation and Exacerbates Acute Lung Injury"],"prefix":"10.1002","volume":"12","author":[{"given":"Ding","family":"Yuan","sequence":"first","affiliation":[{"name":"Emergency Department Medical Key Laboratory of Poisoning Diseases of Henan Province The First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan 450052 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