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Epigenetic suppression of RASAL1 (Ras protein activator like 1), an antifibrotic regulator in fibroblasts, is a key driver of this process. However, the underlying mechanisms are only partially understood. Here, we identify histone deacetylase 3 (HDAC3) as a critical epigenetic suppressor of RASAL1 expression in FMT of renal fibrosis. In mouse models of renal fibrosis induced by unilateral ureteral obstruction and aristolochic acid I, RASAL1 suppression coincided with a preferential increase in HDAC3. Fibroblast-specific\n                    <jats:italic toggle=\"yes\">Hdac3<\/jats:italic>\n                    knockout mice exhibited preserved RASAL1 expression, attenuated FMT, and reduced renal fibrosis compared to wild-type controls. Consistently, pharmacological inhibition of HDAC3 with RGFP966 similarly restored RASAL1 expression, inhibited FMT, and alleviated renal fibrotic pathology. In cultured renal fibroblasts, HDAC3 overexpression or inhibition by RGFP966 inversely affected RASAL1 abundance and major FMT parameters, which was coregulated by the repressive transcriptional factor YY1 (Yin Yang 1). Notably, targeted silencing of RASAL1 abrogated the antifibrotic effects of HDAC3 inhibition both in\u00a0vitro and in\u00a0vivo, underscoring the functional significance of the HDAC3\u2013YY1\u2013RASAL1 axis in FMT and fibrogenesis. Given that FMT is a conserved feature of fibrotic diseases across multiple organs, restoring RASAL1 expression via HDAC3 and YY1 modulation offers promising therapeutic strategies for CKD and potentially broader fibrotic disorders.\n                  <\/jats:p>","DOI":"10.34133\/research.1073","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:05:57Z","timestamp":1765551957000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Suppression of RASAL1 by HDAC3 and Cofactor YY1 Promotes Fibroblast\u2013Myofibroblast Transition and Renal Fibrosis"],"prefix":"10.34133","volume":"9","author":[{"given":"Fang","family":"Chen","sequence":"first","affiliation":[{"name":"Yancheng Key Laboratory of Molecular Epigenetics, Yancheng Medical Research Center of \rNanjing University Medical School, The First People\u2019s Hospital of Yancheng, Yancheng 224006, China."},{"name":"Department of Urology, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Lab of Molecular Medicine, \rNanjing University Medical School, Nanjing 210093, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingbing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First People\u2019s Hospital of Shangqiu","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuren","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengdong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiansong","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijun","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First People\u2019s Hospital of Yancheng, \rThe Yancheng Clinical College of Xuzhou Medical University, Yancheng 224006, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6209-3482","authenticated-orcid":true,"given":"Wangsen","family":"Cao","sequence":"additional","affiliation":[{"name":"Yancheng Key Laboratory of Molecular Epigenetics, Yancheng Medical Research Center of \rNanjing University Medical School, The First People\u2019s Hospital of Yancheng, Yancheng 224006, China."},{"name":"Jiangsu Key Lab of Molecular Medicine, \rNanjing University Medical School, Nanjing 210093, China."},{"name":"Yangzhou Precision Research Institute of Kidney Disease, Yangzhou Key Lab of Kidney Diseases, Department of Nephrology, Northern Jiangsu People\u2019s Hospital, Yangzhou 225001, China."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2018.06.002"},{"issue":"1","key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.kisu.2021.11.003","article-title":"Epidemiology of chronic kidney disease: An update 2022","volume":"12","author":"Kovesdy CP","year":"2022","unstructured":"Kovesdy CP. 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