PFKFB2‐Driven Glycolysis Promotes Dendritic Cell Maturation and Exacerbates Acute Lung Injury

Abstract Acute lung injury (ALI) is a life‐threatening condition with excessive immune activation and dysregulated inflammation. 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‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 2 (PFKFB2) by hypoxia‐inducible factor‐1α (HIF‐1α) enhances glycolysis, drives DC maturation, and exacerbates inflammation, contributing to the pathogenesis of ALI. The findings reveal that HIF‐1α directly binds to the PFKFB2 promoter and drives its transcription, leading to increased glycolysis, accelerated DC maturation, and amplified immune activation. In paraquat (PQ)‐ALI and lipopolysaccharide (LPS)‐ALI mouse models, DC‐specific PFKFB2 knockout and DC‐targeted delivery of HIF‐1α inhibitor‐loaded nanoparticles each significantly suppressed DC maturation and alleviated ALI severity. Analyses of lung tissues from patients with PQ poisoning, secondary bacterial pneumonia (2°BP), and Coronavirus Disease 2019 (COVID‐19), as well as from normal controls, confirmed these findings, showing increased PFKFB2 expression and DC maturation during ALI. These findings highlight the HIF‐1α–PFKFB2 signaling pathway as a critical regulator of glycolysis‐driven DC maturation and immune activation, offering novel insights into immunometabolic regulation and a promising therapeutic target for ALI.