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Atherogenesis is dependent on lipid homeostasis and inflammatory processes, with the formation of lipid-laden, macrophage-derived foam cells (MDFC) essential for atherosclerotic lesion progression. Elevated cholesterol levels within lipid rafts trigger heightened pro-inflammatory responses in macrophages via Toll-like receptor 9 (TLR9). Artesunate (ART), an artemisinin derivative sourced from Artemisia annua, exhibits therapeutic potential in modulating inflammation and autoimmune conditions. Nonetheless, its impact and mechanisms in SLE-associated AS (SLE-AS) remain largely unexplored. Our investigation demonstrated that ART could effectively ameliorate lupus-like symptoms and atherosclerotic plaque development in SLE-AS mice. Moreover, ART enhanced cholesterol efflux from MDFC by upregulating ABCA1, ABCG1, and SR-B1 both in vivo and in vitro. Moreover, ART reduced cholesterol accumulation in bone marrow-derived macrophages (BMDMs), thereby diminishing TLR9 recruitment to lipid rafts. ART also suppressed TLR9 expression and its downstream effectors in the kidney and aorta of SLE-AS mice, attenuating the TLR9-mediated inflammatory cascade in CPG2395 (ODN2395)-stimulated macrophages. Through bioinformatics analysis and experimental validation, PPAR\u03b3 was identified as a pivotal downstream mediator of ART in macrophages. Depleting PPAR\u03b3 levels reduced the expression of ABCA1, ABCG1, and SR-B1 in macrophages, consequently impeding cholesterol efflux. In conclusion, these findings suggest that ART ameliorates SLE-AS by restoring cholesterol homeostasis through the PPAR\u03b3-ABCA1\/ABCG1\/SR-B1 pathway and suppressing lipid raft-driven TLR9\/MyD88 inflammation.<\/jats:p>","DOI":"10.3390\/biom15081078","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T14:40:02Z","timestamp":1753454402000},"page":"1078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Artesunate Ameliorates SLE Atherosclerosis Through PPAR\u03b3-Driven Cholesterol Efflux Restoration and Disruption of Lipid Raft-Organized TLR9\/MyD88 Signaling Pathway"],"prefix":"10.3390","volume":"15","author":[{"given":"Miao","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"},{"name":"Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Pan","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"},{"name":"Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfang","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"},{"name":"Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou 310000, China"},{"name":"Zhejiang Provincial Zhongshan Hospital, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kairong","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"},{"name":"Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyu","family":"Tian","sequence":"additional","affiliation":[{"name":"Ningbo Taikang Hospital, Ningbo 315000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Qiu","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengping","family":"Wen","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"},{"name":"Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5823-2239","authenticated-orcid":false,"given":"Juan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310000, China"},{"name":"Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s00281-014-0428-6","article-title":"The pathogenesis and diagnosis of systemic lupus erythematosus: Still not resolved","volume":"36","author":"Rekvig","year":"2014","journal-title":"Semin. 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