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We demonstrate that macrophage oxLDL-derived superoxide modulates mitochondrial metabolic reprogramming, facilitating foam cell formation. Mechanistically, mitochondrial superoxide drives signal transducers and activators of transcription 5 (STAT5) activation, leading to reduced tricarboxylic acid cycle activity. In parallel, mitochondrial superoxide enhances chromatin accessibility at STAT5 target genes, establishing a distinct STAT5 signaling signature in foam cells ex vivo and in human and mouse plaques in vivo. Inhibition of STAT5 during atherosclerosis progression prevents the differentiation of macrophages to mature Trem2\n            <jats:sup>hi<\/jats:sup>\n            Gpnmb\n            <jats:sup>hi<\/jats:sup>\n            foam cells. Collectively, our data describe an oxLDL-induced, mitochondrial superoxide\u2013dependent STAT5 activation that leads to a self-amplifying feedback loop of reciprocal mitochondrial superoxide production and STAT5 activation, ultimately driving macrophage-to-foam cell transition.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adw9952","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:59:06Z","timestamp":1756317546000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3229-4520","authenticated-orcid":true,"given":"Laura","family":"Boccuni","sequence":"first","affiliation":[{"name":"Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria."},{"name":"Department of Internal Medicine II\/Cardiology, Medical University of Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frieda","family":"Marka","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-3533","authenticated-orcid":true,"given":"Manuel","family":"Salzmann","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research and Translational Surgery, Medical University of Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5446-9136","authenticated-orcid":true,"given":"Alessia","family":"Schirripa","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7971-9629","authenticated-orcid":true,"given":"Elisabeth","family":"Ableitner","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7354-5763","authenticated-orcid":true,"given":"Magdalena","family":"Siller","sequence":"additional","affiliation":[{"name":"CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria."},{"name":"Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3210-6973","authenticated-orcid":true,"given":"Mira","family":"Brekalo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology, Medical University of Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6874-5349","authenticated-orcid":true,"given":"Patrick","family":"Haider","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology, Medical University of Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4285-5416","authenticated-orcid":true,"given":"Stefan","family":"Stojkovic","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology, Medical University of Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1407-4185","authenticated-orcid":true,"given":"Christoph","family":"Neumayer","sequence":"additional","affiliation":[{"name":"Division of General Surgery, Medical University of Vienna, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-1749","authenticated-orcid":true,"given":"Tiit","family":"\u00d6rd","sequence":"additional","affiliation":[{"name":"A.I. 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