OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-κB/HIF-1β-dependent metabolic rewiring.
6 affiliations
- 1Laboratory of Cancer Precision Medicine, Institute of Translational Research, The First Hospital of Jilin University, Changchun, Jilin, China.
- 2Jilin Provincial Key Laboratory of Precision Medicine for Age-Related Diseases, Changchun, China.
- 3Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China.
- 4Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
- 5Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China.
- 6Department of Hematology and Oncology, Shanghai Jing'an District Zhabei Central Hospital, Shanghai, China.
Abstract
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 in vitro and ex vivo experiments to characterize the phenotypic, metabolic, and functional changes.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 ARNT (encoding HIF-1β) recapitulated the effects of NF-κB inhibition, positioning HIF-1β downstream of the NF-κB pathway. Furthermore, inhibition of NF-κB also attenuated oxLDL-induced inflammasome activation and priming for a heightened secondary response, impaired the foam cell-forming capacity of OAMs, and moderately affected efferocytosis.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.
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BibTeX
@article{lan2026oxldl,
title = {{OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-κB/HIF-1β-dependent metabolic rewiring.}},
author = {Maozhuo Lan and Yangyang Zhou and Yue Sun and Xingcheng Yi and Mengtuan Long and Dirk M Hermann and Fengyan Jin and Yun Dai},
journal = {Frontiers in cardiovascular medicine},
year = {2026},
month = oct,
doi = {10.3389/fcvm.2026.1957621},
url = {https://europepmc.org/article/MED/42908577},
note = {CC BY},
}
RIS
TY - JOUR
TI - OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-κB/HIF-1β-dependent metabolic rewiring.
AU - Maozhuo Lan
AU - Yangyang Zhou
AU - Yue Sun
AU - Xingcheng Yi
AU - Mengtuan Long
AU - Dirk M Hermann
AU - Fengyan Jin
AU - Yun Dai
PY - 2026
DA - 2026/10/07
JO - Frontiers in cardiovascular medicine
DO - 10.3389/fcvm.2026.1957621
UR - https://europepmc.org/article/MED/42908577
AB - 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 in vitro and ex vivo experiments to characterize the phenotypic, metabolic, and functional changes.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 ARNT (encoding HIF-1β) recapitulated the effects of NF-κB inhibition, positioning HIF-1β downstream of the NF-κB pathway. Furthermore, inhibition of NF-κB also attenuated oxLDL-induced inflammasome activation and priming for a heightened secondary response, impaired the foam cell-forming capacity of OAMs, and moderately affected efferocytosis.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.
SN - 2297-055X
ER -