{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:27:12Z","timestamp":1793395632430,"version":"4.5.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370364"],"award-info":[{"award-number":["82370364"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82300414"],"award-info":[{"award-number":["82300414"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170424"],"award-info":[{"award-number":["82170424"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20231049"],"award-info":[{"award-number":["BK20231049"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["JUSRP124036"],"award-info":[{"award-number":["JUSRP124036"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004028","name":"Jiangnan University","doi-asserted-by":"publisher","award":["LCYJ202306"],"award-info":[{"award-number":["LCYJ202306"]}],"id":[{"id":"10.13039\/501100004028","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n A significant increase in mitochondrial fatty acid oxidation (FAO) is now increasingly recognized as one of the metabolic alterations in diabetic cardiomyopathy (DCM). However, the molecular mechanisms underlying mitochondrial FAO impairment in DCM remain to be fully elucidated.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A type 2 diabetes (T2D) mouse model was established by a combination of high\u2010fat diet (HFD) and streptozotocin (STZ) injection. Neonatal rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (HP) to simulate diabetic cardiac injury. Gain\u2010 and loss\u2010of\u2010function approaches and RNA sequencing were utilized to investigate the role and mechanism of 2,4\u2010dienoyl\u2010CoA reductase 1 (Decr1) in DCM.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n By integrating the genomic data available in the Gene Expression Omnibus (GEO) with DCM rodents, we found that the transcriptional level of Decr1 was consistently upregulated in DCM (+255% for diabetic heart,\n p<\/jats:italic>\n \u2009<\u20090.0001; +281% for diabetic cells,\n p<\/jats:italic>\n \u2009<\u20090.0001). Cardiomyocytes\u2010specific knockdown of Decr1 preserved cardiac function (+41% for EF,\n p<\/jats:italic>\n \u2009<\u20090.0001; +24% for FS,\n p<\/jats:italic>\n \u2009=\u20090.0052), inhibited cardiac hypertrophy (\u221234%,\n p<\/jats:italic>\n \u2009<\u20090.0001), fibrosis (\u221269%,\n p<\/jats:italic>\n \u2009<\u20090.0001), apoptosis (\u221256%,\n p<\/jats:italic>\n \u2009<\u20090.0001) and oxidative damage (\u221259%,\n p<\/jats:italic>\n \u2009<\u20090.0001) in DCM mice, while cardiomyocytes\u2010specific overexpression of Decr1 aggravated DCM (\u221228% for EF,\n p<\/jats:italic>\n \u2009=\u20090.0347; \u221217% for FS,\n p<\/jats:italic>\n \u2009=\u20090.0014). Deletion of Decr1 prevented high glucose\/palmitate (HG\/HP)\u2010induced hypertrophy (\u221222%,\n p<\/jats:italic>\n \u2009=\u20090.0006), mitochondrial dysfunction and apoptosis (\u221274%,\n p<\/jats:italic>\n \u2009<\u20090.0001) in cultured cardiomyocytes. Furthermore, RNA sequencing and functional analysis showed that Decr1 interacted with and upregulated pyruvate dehydrogenase kinase 4 (PDK4) in injured cardiomyocytes, and overexpression of PDK4 eliminated the benefits of Decr1 downregulation in DCM (\u221220% for EF,\n p<\/jats:italic>\n \u2009=\u20090.0071; \u221228% for FS,\n p<\/jats:italic>\n \u2009=\u20090.0022). Mechanistically, PDK4 acted as a kinase that induced phosphorylation and mitochondrial translocation of HDAC3. In the mitochondria, HDAC3 mediated the deacetylation of dehydrogenase trifunctional multienzyme complex \u03b1 subunit (HADHA), contributing to excessive mitochondrial FAO and subsequent cardiac injury. From a screening of 256 natural products, we identified Atranorin and Kurarinone as potential inhibitors of Decr1, both demonstrating protective effects against DCM (Atranorin, +21% for EF,\n p<\/jats:italic>\n \u2009=\u20090.0134; +24% for FS,\n p<\/jats:italic>\n \u2009=\u20090.0006; Kurarinone, +20% for EF,\n p<\/jats:italic>\n \u2009=\u20090.0183; +27% for FS,\n p<\/jats:italic>\n \u2009=\u20090.0001).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our study delineates a molecular mechanism by which Decr1 potentiated higher mitochondrial lipid oxidation and cardiac damage by enhancing HADHA deacetylation through the PDK4\/HDAC3 signalling pathway.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13761","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:54:46Z","timestamp":1741758886000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Therapeutic Targeting of Decr1 Ameliorates Cardiomyopathy by Suppressing Mitochondrial Fatty Acid Oxidation in Diabetic Mice"],"prefix":"10.1002","volume":"16","author":[{"given":"Qing\u2010Bo","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Endocrinology Affiliated Hospital of Jiangnan University, Jiangnan University Wuxi Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He\u2010Ting","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmacy Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University Yantai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Bao","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Affiliated Hospital of Jiangnan University, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin\u2010Yu","family":"Meng","sequence":"additional","affiliation":[{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao\u2010Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An\u2010Jing","family":"Xu","sequence":"additional","affiliation":[{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen\u2010Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi 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Reproductive Health and Genetic Diseases Wuxi Maternity and Child Health Care Hospital, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Affiliated Hospital of Jiangnan University, Jiangnan University Wuxi Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Cardiology the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Nanjing Medical University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Xue","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Affiliated Hospital of Jiangnan University, Jiangnan University Wuxi Jiangsu China"},{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7791-5335","authenticated-orcid":false,"given":"Hai\u2010Jian","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Affiliated Hospital of Jiangnan University, Jiangnan University Wuxi Jiangsu China"},{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases School of Medicine, Jiangnan University Wuxi China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ncrna.2024.06.011"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-0339-2"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2021.154910"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-020-00835-7"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.983713"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2024.155977"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15418"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000433"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2016.08.021"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/461967"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2022.10.014"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-023-00510-4"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1125866"},{"key":"e_1_2_8_15_1","first-page":"1","article-title":"Leucine\u2010Rich Repeat Kinase 2 Exacerbates Neuronal Cytotoxicity Through Phosphorylation of Histone Deacetylase 3 and Histone Deacetylation","volume":"26","author":"Han K. A.","year":"2017","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep16577"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/2159460"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.705154"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-03928-8"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S405327"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107931"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13761","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.13761","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13761","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T04:13:31Z","timestamp":1771215211000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.13761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,7]]},"references-count":20,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1002\/jcsm.13761"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.13761","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,7]]},"assertion":[{"value":"2024-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13761"}}