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However, the underlying molecular mechanisms remain incompletely understood. This study investigated the role of the macrophage-specific fat mass and obesity-associated gene (FTO) in atherogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used an adeno-associated virus serotype 9 (AAV9) vector under the control of the F4\/80 promoter to overexpress FTO in macrophages. The functional roles of FTO and its molecular interactions were investigated through Western blotting, RT-qPCR, coimmunoprecipitation, immunofluorescence, and MeRIP-qPCR assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FTO expression was shown to be specifically reduced in macrophages. In primary peritoneal macrophages and RAW264.7 cells, reduced FTO expression increased lipid uptake and deposition. Overexpressing FTO significantly reduced high-fat diet (HFD)-induced atherosclerotic plaque formation and lipid accumulation in vivo. Mechanistically, FTO deficiency increased the mRNA stability of phosphofurin acidic cluster sorting protein 2 (\n                      <jats:italic>PACS2<\/jats:italic>\n                      ) in an N6-methyladenosine (m\n                      <jats:sup>6<\/jats:sup>\n                      A)-dependent manner, thereby leading to elevated PACS2 protein levels and subsequent activation of the PPAR\u03b3 pathway. This in turn resulted in increased expression of CD36 and PLIN2, which promoted lipid uptake and lipid droplet formation, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify a novel macrophage FTO-PACS2-PPAR\u03b3 regulatory axis that plays a key role in lipid dysregulation and atherogenesis, thus highlighting FTO as a potential therapeutic target for atherosclerosis and related cardiovascular diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08076-3","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T16:36:44Z","timestamp":1774975004000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Macrophage FTO deficiency accelerates atherosclerosis via PACS2-mediated activation of the PPAR\u03b3 lipid signaling pathway"],"prefix":"10.1186","volume":"24","author":[{"given":"Jie","family":"Ouyang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zishun","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijiao","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiyi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanjun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex F.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8005-142X","authenticated-orcid":false,"given":"Hongwei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"8076_CR1","doi-asserted-by":"publisher","first-page":"1083875","DOI":"10.3389\/fphar.2023.1083875","volume":"14","author":"Q Wu","year":"2023","unstructured":"Wu Q, Lv Q, Liu X, Ye X, Cao L, Wang M, et al. 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