OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-κB/HIF-1β-dependent metabolic rewiring.

Introduction: Dysregulated lipid metabolism and inflammation are two core pathological drivers of atherosclerosis; however, their causal interplay remains incompletely elucidated. Macrophages play a central role in sustaining unresolved inflammation, which is a hallmark of atherosclerosis. Recent single-cell RNA-sequencing studies have revealed phenotypic heterogeneity among macrophages in atherosclerotic lesions, encompassing two key pro-atherogenic subsets: pro-inflammatory and foam cell-forming macrophages. Given that oxidized low-density lipoprotein (oxLDL) is a pivotal pathological factor in atherosclerosis, we investigated whether and how oxLDL drives the reprogramming of macrophages toward a pro-atherogenic phenotype. Methods: Transcriptomic analyses were performed on macrophages exposed to oxLDL, followed by a series of Results: We identified a macrophage phenotype, named oxLDL-activated macrophages (OAMs), which displayed significant molecular and functional similarities to both pro-inflammatory and foam cell-forming macrophages. OxLDL-induced macrophage reprogramming was associated with a metabolic paradigm shift from oxidative phosphorylation to glycolysis, which was abrogated by inhibition of NF-κB activation, accompanied by polarization toward an anti-inflammatory phenotype. Knockdown of Conclusions: Our findings demonstrate that oxLDL drives macrophage polarization toward a pro-atherogenic (pro-inflammatory and foam cell-prone) phenotype via metabolic rewiring and transcriptional remodeling mediated by HIF-1β-dependent crosstalk between the NF-κB and HIF pathways. This signaling axis may serve as a potential therapeutic target for atherosclerosis.