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Mitochondrial uncoupling protein 2 (UCP2), proposed to facilitate metabolite transport, is involved in regulating inflammation and glucose metabolism in macrophages. However, its significance and regulatory mechanism in subsets of macrophages with distinct metabolic profiles remain unclear. In this study, we demonstrate that under physiological nutrient conditions, inflammatory stimuli in classically activated macrophages (via LPS) reduce UCP2 expression in line with decreased oxygen consumption rates, indicating mitochondrial suppression. In contrast, alternatively activated macrophages (via IL4) displayed higher UCP2 levels and enhanced respiration. Under glucose deprivation, LPS\u2010stimulated macrophages retained mitochondrial activity despite lower UCP2 levels. Blocking pyruvate entry into the mitochondria reduced UCP2 expression, highlighting the connection between glycolysis and mitochondrial metabolism. Mimicking the hypoxic milieu characteristic of LPS\u2010activated macrophages through CoCl\n                    <jats:sub>2<\/jats:sub>\n                    treatment of IL\u20104\u2010activated macrophages resulted in decreased UCP2 expression, suggesting that hypoxia broadly mediates UCP2 suppression in macrophages. Overall, our findings suggest that UCP2 protein levels are modulated by metabolic alterations in macrophages, with pyruvate acting as a key regulator of UCP2 abundance. This emphasizes the importance of UCP2 in linking glycolysis with mitochondrial metabolism, providing insights for developing therapeutic strategies for diseases involving immunometabolic dysregulation.\n                  <\/jats:p>","DOI":"10.1002\/eji.70218","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T08:07:31Z","timestamp":1780992451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pro\u2010 and Anti\u2010Inflammatory Macrophages Adjust UCP2 Protein Levels Based on Their Intrinsic Metabolism and Available Metabolites"],"prefix":"10.1002","volume":"56","author":[{"given":"Jila","family":"Nasirzade","sequence":"first","affiliation":[{"name":"Physiology and Biophysics Department of Biological Science and Pathobiology University of Veterinary Medicine  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Sternberg","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics Department of Biological Science and Pathobiology University of Veterinary Medicine  Vienna Austria"},{"name":"Department of Nutritional Sciences Faculty of Life Sciences University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Faculty of Life Sciences University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roko","family":"Sango","sequence":"additional","affiliation":[{"name":"Center of Pathobiochemistry and Genetics Institute of Medical Genetics Medical University of Vienna  Vienna Austria"},{"name":"Centre for Microbiology and Environmental Systems Science University of Vienna  Vienna Austria"},{"name":"Doctoral School in Microbiology and Environmental Science University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taraneh","family":"Beikbaghban","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics Department of Biological Science and Pathobiology University of Veterinary Medicine  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kolbe","sequence":"additional","affiliation":[{"name":"Laboratory Animal Medicine Department of Biological Science and Pathobiology University of Veterinary Medicine  Vienna Austria"},{"name":"Department of Agricultural Sciences University of Natural Resources and Life Sciences  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Rattei","sequence":"additional","affiliation":[{"name":"Centre for Microbiology and Environmental Systems Science University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-0797","authenticated-orcid":false,"given":"Thomas","family":"Weichhart","sequence":"additional","affiliation":[{"name":"Center of Pathobiochemistry and Genetics Institute of Medical Genetics Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0604-5950","authenticated-orcid":false,"given":"Elena E.","family":"Pohl","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics Department of Biological Science and Pathobiology University of Veterinary Medicine  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21363"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76744"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.68"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.005"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41387\u2010021\u201000162\u20103"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.74690"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397\u2010269"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00470"},{"key":"e_1_2_12_10_1","doi-asserted-by":"crossref","unstructured":"K. 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