{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:50:11Z","timestamp":1791352211782,"version":"4.3.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic analyses were performed on macrophages exposed to oxLDL, followed by a series of\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>ex vivo<\/jats:italic>\n                      experiments to characterize the phenotypic, metabolic, and functional changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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-\u03baB activation, accompanied by polarization toward an anti-inflammatory phenotype. Knockdown of\n                      <jats:italic>ARNT<\/jats:italic>\n                      (encoding HIF-1\u03b2) recapitulated the effects of NF-\u03baB inhibition, positioning HIF-1\u03b2 downstream of the NF-\u03baB pathway. Furthermore, inhibition of NF-\u03baB 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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-1\u03b2-dependent crosstalk between the NF-\u03baB and HIF pathways. This signaling axis may serve as a potential therapeutic target for atherosclerosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1957621","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:53:40Z","timestamp":1791348820000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-\u03baB\/HIF-1\u03b2-dependent metabolic rewiring"],"prefix":"10.3389","volume":"13","author":[{"given":"Maozhuo","family":"Lan","sequence":"first","affiliation":[{"name":"Laboratory of Cancer Precision Medicine, Institute of Translational Research, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]},{"name":"Jilin Provincial Key Laboratory of Precision Medicine for Age-Related Diseases","place":["Changchun, 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