PFKFB3 Mediated Glycolytic Reprogramming Drives Vascular Endothelial Injury Under Chronic Intermittent Hypoxia

Metabolic-inflammatory crosstalk is a hallmark of cardiovascular pathogenesis. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for cardiovascular diseases. While endothelial inflammation driven by CIH is pivotal in disease progression, the underlying metabolic mechanisms remain poorly defined. Our research shows that phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic activator, is markedly upregulated in endothelial cells (ECs) exposed to CIH, correlating with enhanced glycolysis, suppressed mitochondrial respiration, and amplified inflammatory responses. Endothelial-specific PFKFB3 deficiency or pharmacological suppression of PFKFB3 restores the glycolytic balance and alleviates vascular endothelial injury. Mechanistically, CIH enhances the expression of hypoxia-inducible factor 1α (HIF-1α), which regulates PFKFB3 expression. PFKFB3-induced production of lactate further promotes H3K18 lactylation (H3K18la), which in turn binds the PFKFB3 promoter, forming a positive-feedback loop. Disruption of the HIF-1α/PFKFB3 axis alleviates the inflammatory and glycolytic signatures of ECs. In conclusion, our findings identify PFKFB3 as a critical metabolic driver of endothelial inflammation under CIH, orchestrated through a HIF-1α-PFKFB3-H3K18la loop. These findings reveal novel pathogenic insights and potential therapeutic targets for OSA-associated cardiovascular diseases.