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

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.