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J. Chin. Med."],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>The accumulation of aging cells significantly contributes to chronic inflammatory diseases such as atherosclerosis. Human carotid artery single-cell sequencing has shown that large numbers of aging foam cells are present in the plaques of human patients. Berberine (BBR) has been shown to inhibit cell senescence, however, the mechanisms involved in its treatment of atherosclerotic senescence have not yet been determined. Changes in plaque morphology and blood chemistry were observed in ApoE[Formula: see text] mice fed with a high-fat diet before and after BBR treatment. Inflammatory proteins linked to the senescence-associated secretory phenotypes (SASP) were detected in RAW264.7 and peritoneal macrophage-derived foam cells. Smart-seq analysis was used to explore the pathways associated with BBR therapy for atherosclerosis. Finally, the effect of lentivirus-mediated knockdown of RXR\u03b1 in macrophages in plaques on atherosclerosis treatment with BBR was determined. We found that BBR reduced inflammation linked to SASP in atherosclerosis through the RXR\u03b1\/PPAR\u03b3\/NEDD4 signaling pathway. BBR increased GATA4 binding to p62, promoted ubiquitination, and inhibited SASP-associated protein production in RAW264.7 and peritoneal macrophage-derived foam cells. Mechanistically, according to the Smart-seq results, BBR activated RXR\u03b1 and PPAR\u03b3, synergistically increased NEDD4 transcription levels, and promoted ubiquitination-mediated degradation of the GATA4\/p62 complex. Additionally, the anti-aging impact of BBR on atherosclerosis was negated when macrophage-specific RXR\u03b1 was knocked down using lentivirus (pLVCD68-shRNA RXR\u03b1) in ApoE[Formula: see text] mice. BBR activated PPAR\u03b3 through RXR\u03b1-PPAR\u03b3 immune complex in macrophage-derived foam cells, increased NEDD4 transcriptional activity, promoted ubiquitination of GATA4-p62 complex, and inhibited SASP-related inflammation. These findings suggest the potential of BBR as a novel approach to addressing SASP-associated inflammation in atherosclerosis.<\/jats:p>","DOI":"10.1142\/s0192415x25500107","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T03:17:34Z","timestamp":1737343054000},"page":"251-283","source":"Crossref","is-referenced-by-count":10,"title":["Berberine Inhibited SASP-Related Inflammation through RXR\u03b1\/PPAR\u03b3\/NEDD4 Pathway in Atherosclerosis"],"prefix":"10.1142","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9488-1295","authenticated-orcid":false,"given":"Yinghong","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Tianjin Medical University 22 Qixiangtai Road, Heping District, Tianjin 300070, P. R. China"},{"name":"Department of Pathophysiology, Harbin Medical University 157 Baojian Road, Nangang District, Harbin 150081, P. R. 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