FBP1/HIF-1α Axis mediates macrophage metabolic reprogramming and serves as diagnostic biomarkers in atherosclerosis

Atherosclerosis (AS)，a major global cause of cardiovascular mortality，is characterized by significant metabolic reprogramming of plaque macrophages in response to a hostile microenvironment containing cytokines, oxidized lipids, and hypoxia. Macrophage metabolic reprogramming, marked by shifts in glycolysis, fatty acid, and amino acid metabolism has emerged as a critical contributor to chronic inflammatory diseases. This study explores the role of fructose-1,6-bisphosphatase 1 (FBP1) in this process and its functional interplay with hypoxia-inducible factor-1α (HIF-1α). Clinically, FBP1 and HIF-1α levels were significantly elevated in peripheral blood mononuclear cells (PBMCs) and serum from AS patients. ROC analysis indicated their strong potential as diagnostic biomarkers. These findings were corroborated in high-fat diet-fed mice and ox-LDL-stimulated macrophages, which showed increased FBP1 and HIF-1α expression in atherosclerotic lesions and immune cells. FBP1 overexpression mitigated ox-LDL-induced metabolic reprogramming, evidenced by reduced lactate production, reactive oxygen species (ROS) generation, and lipid droplet accumulation. Conversely, FBP1 suppression exacerbated these metabolic alterations. Mechanistically, FBP1 directly interacted with and inhibited the expression of HIF-1α. Inhibition of HIF-1α reverses the exacerbation of cellular metabolic reprogramming induced by FBP1 inhibition. In summary, the results demonstrate FBP1/ HIF-1α axis as mediator of macrophage metabolic reprogramming in AS, highlighting its dual significance as a contributor to disease pathogenesis and a promising basis for clinical diagnosis.