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ST32da derived from Salvia miltiorrhiza (a well-recognized Traditional Chinese Medicine) induces activating transcription factor 3 (ATF3), a negative regulator of inflammation and metabolic stress. However, the effects of ST32da on obesity-related DN remain underexplored. We investigated the therapeutic potential of ST32da, a synthetic ATF3 inducer derived from Salvia miltiorrhiza, in mitigating obesity-related DN in both in vivo and in vitro models. The Nephroseq database analysis was performed to explore the relationship between Atf3 expression and DN progression. ST32da was administered to db\/db knockout and DBA mice to establish obesity-related DN models, and a high-fat diet (HFD)-induced mouse model of obesity-related DN was used to investigate the effects of Atf3 knockout. Molecular and biochemical analyses were conducted in cultured mesangial cells to elucidate the underlying mechanisms. ATF3 deficiency worsened obesity-related DN, increasing glomerular fibrosis, mortality, and inflammation. ST32da restored ATF3 levels and reduced renal injury, glomerular expansion, and pro-inflammatory cytokine expression (e.g., IL-6, TGF\u03b2, TNF\u03b1). ST32da-treated mice exhibited reduced hepatic lipid accumulation and improved serum lipid profiles. In mesangial cells, ST32da localized to the cytoplasm and increased ATF3 activity, which suppressed RARRES1 expression and cytokine signaling. Mechanistically, ATF3 interacted with HDAC2 to repress NF-\u03baB\u2014dependent inflammatory gene expression. The findings suggest ST32da is a promising therapeutic candidate for obesity-related DN and associated metabolic disturbances, acting through ATF3 induction to suppress renal inflammation, lipotoxicity, and fibrosis.<\/jats:p>","DOI":"10.3390\/cells14231893","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:39:43Z","timestamp":1764679183000},"page":"1893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ST32da, a Novel Salvia miltiorrhiza-Derived ATF3 Inducer, Alleviates Obesity-Related Diabetic Nephropathy in Mouse Models"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8286-802X","authenticated-orcid":false,"given":"Hsi-Hsien","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, No. 252, Wuxing St., Xinyi Dist., Taipei 110, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei 110, Taiwan"},{"name":"TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Medical University Hospital, No. 252, Wuxing St., Xinyi Dist., Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ling","family":"Tseng","sequence":"additional","affiliation":[{"name":"CardioVascular Research Center, Buddhist Tzu Chi General Hospital, No. 707, Zhongyang Rd., Sec. 3, Hualien 97004, Taiwan"},{"name":"Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan"},{"name":"Department of Basic Medical Sciences, College of Nursing, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiao-Fen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ting","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tu Tuan","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Thai Nguyen University of Medicine and Pharmacy, Thai Nguyen 241-17, Vietnam"},{"name":"Department of Nephro-Urology and Dialysis, Thai Nguyen National Hospital, Thai Nguyen 241-24, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh-Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei 110, Taiwan"},{"name":"TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No. 111, Sec. 3, Xinglong Rd., Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Samsu, N. 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