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Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. Objectives: This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. Methods: We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. Results: Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPAR\u03b3) was identified as a key regulator through gene screening. AcAc primarily regulated PPAR\u03b3 expression, and knocking down PPAR\u03b3 significantly aggravated HF progression. Conclusions: The ability of AcAc to restore LD levels and regulate PPAR\u03b3 suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation.<\/jats:p>","DOI":"10.3390\/ph18020219","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T04:47:31Z","timestamp":1738817251000},"page":"219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells"],"prefix":"10.3390","volume":"18","author":[{"given":"Ya","family":"Zhou","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feixia","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2625-6667","authenticated-orcid":false,"given":"Mengru","family":"Hu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwei","family":"Xia","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of hepatic fibrosis and its regression","volume":"18","author":"Kisseleva","year":"2021","journal-title":"Nat. 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