{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:04:49Z","timestamp":1789621489025,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Abstract Background<\/jats:title>\n                    <jats:p>Mitochondrial dysfunction is increasingly recognized as a driver of maladaptive macrophage polarization in atherosclerosis (AS), but the mitochondrial genes that shape disease-relevant macrophage states remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated weighted gene co-expression network analysis (WGCNA), machine learning, two-sample Mendelian randomization (two-sample MR), bulk transcriptomics, single-cell analysis, disease-level validation, single-cell mediation, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      perturbation to identify macrophage-relevant mitochondrial regulators in AS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eight candidate genes were consistently prioritized by WGCNA and machine learning; among them, microsomal glutathione S-transferase 3 (MGST3) showed the strongest protective genetic signal. Two-sample MR supported a protective association between genetically predicted MGST3 expression and coronary artery disease\/coronary heart disease risk (training set OR\u00a0=\u00a00.989, 95% CI 0.978-0.999, P\u00a0=\u00a00.042; test set OR\u00a0=\u00a00.977, 95% CI 0.960-0.995, P\u00a0=\u00a00.013). Human carotid plaque validation confirmed reduced MGST3 at both mRNA and protein levels in AS lesions. Notably, despite this whole-plaque downregulation, single-cell and disease-level analyses revealed an expanded MGST3-high M2-like macrophage state in AS, suggesting a compensatory protective macrophage program within diseased plaques. MGST3-high M2-like cells displayed an OXPHOS-oriented, antioxidant, and less inflammatory transcriptional state, acted as an active signaling population, and showed higher composite MitoHealth scores. Single-cell mediation analysis further indicated that MitoHealth statistically links higher MGST3 expression to lower inflammatory activity, lower M1-like polarization, and lower atherogenic macrophage programming. In M2-polarized macrophages, MGST3 knockdown reduced M2-associated and mitochondrial\/antioxidant transcripts while increasing pro-inflammatory transcripts, providing transcript-level functional support. PheWAS analysis detected no significant phenotype associations at the predefined threshold.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings define MGST3 as a marker of a mitochondrial-health-associated M2-like macrophage state that appears expanded within AS plaques despite reduced whole-plaque MGST3 expression. The MGST3-MitoHealth axis may represent a compensatory macrophage program linked to mitochondrial preservation and lower pro-atherogenic activation, warranting further diagnostic and therapeutic investigation in AS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1864957","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:46:49Z","timestamp":1789620409000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MGST3 defines a mitochondrial-health-associated M2 macrophage state in atherosclerosis: integrative multi-omics, single-cell mediation, and functional validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Qiong-Chao","family":"Zou","sequence":"first","affiliation":[{"name":"Cardiology Department, Hunan Provincial People\u2019s Hospital","place":["Changsha Hunan, China"]},{"name":"Clinical Research Center for Heart Failure in Hunan Province","place":["Changsha, Hunan, China"]},{"name":"Institute of Cardiovascular Epidemiology, Hunan Provincial People\u2019s Hospital","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Hong","family":"Yi","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Epidemiology, Hunan Provincial People\u2019s Hospital","place":["Changsha, Hunan, China"]},{"name":"Department of Cardiology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People\u2019s Hospital)","place":["Changsha, Hunan, China"]},{"name":"School of Medicine, Hunan Normal University","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"He","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hunan Provincial People\u2019s Hospital","place":["Changsha Hunan, China"]},{"name":"Clinical Research Center for Heart Failure in Hunan Province","place":["Changsha, Hunan, China"]},{"name":"Institute of Cardiovascular Epidemiology, Hunan Provincial People\u2019s Hospital","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Jing","family":"Rong","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hunan Provincial People\u2019s Hospital","place":["Changsha Hunan, China"]},{"name":"Clinical Research Center for Heart Failure in Hunan Province","place":["Changsha, Hunan, China"]},{"name":"Institute of Cardiovascular Epidemiology, Hunan Provincial People\u2019s Hospital","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Wei","family":"Pan","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hunan Provincial People\u2019s Hospital","place":["Changsha Hunan, China"]},{"name":"Clinical Research Center for Heart Failure in Hunan Province","place":["Changsha, Hunan, China"]},{"name":"Institute of Cardiovascular Epidemiology, Hunan Provincial People\u2019s Hospital","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Fei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hunan Provincial People\u2019s Hospital","place":["Changsha Hunan, China"]},{"name":"Clinical Research Center for Heart Failure in Hunan Province","place":["Changsha, Hunan, China"]},{"name":"Institute of Cardiovascular Epidemiology, Hunan Provincial People\u2019s Hospital","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-024-01023-z","article-title":"Targeting immune cell recruitment in atherosclerosis","volume":"21","author":"D\u00f6ring","year":"2024","journal-title":"Nat Rev Cardiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00584-1","article-title":"How the immune system shapes atherosclerosis: roles of innate and adaptive immunity","volume":"22","author":"Roy","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03392-8","article-title":"The changing landscape of atherosclerosis","volume":"592","author":"Libby","year":"2021","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00769-8","article-title":"Evolving concepts of the vulnerable atherosclerotic plaque and the vulnerable patient: implications for patient care and future research","volume":"20","author":"Gaba","year":"2023","journal-title":"Nat Rev Cardiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1161\/atvbaha.123.319932","article-title":"Subclinical atherosclerosis: Part 1: What is it? 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