{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:49:07Z","timestamp":1782485347899,"version":"3.54.5"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ischemic cardiomyopathy (ICM), a leading cause of heart failure, is characterised by complex cellular heterogeneity and a dysregulated microenvironment. A systematic computational dissection of its molecular mechanisms and a coherent pipeline from discovery to potential therapeutics is currently lacking. We integrated single\u2010cell RNA sequencing (scRNA\u2010seq) data from ICM patients with four independent bulk transcriptomic cohorts. A cardiac cellular atlas was constructed, and candidate genes were filtered through differential expression analysis. Subsequently, a benchmark of 127 machine learning algorithm\u2010feature selection combinations was performed to identify robust diagnostic hub genes. Their functions were validated at single\u2010cell resolution via UCell scoring, pseudotime trajectory analysis, and virtual knockout perturbations using scTenifoldKnk. The immune infiltration landscape was assessed using CIBERSORT and MCP\u2010counter. Finally, computational drug repositioning and molecular docking were employed to screen for potential compounds targeting the hub genes. Machine learning identified a core 5\u2010gene signature (\n                    <jats:italic>NPPA, HTRA1, LUM, ASPN<\/jats:italic>\n                    , and\n                    <jats:italic>OGN<\/jats:italic>\n                    ) demonstrating excellent diagnostic performance across independent datasets (AUC &gt;\u20090.83). Single\u2010cell analysis revealed that these genes were most abundantly expressed in fibroblasts and were consistently upregulated in ICM. Pseudotemporal trajectory analysis illustrated their dynamic expression patterns. Virtual knockout and functional enrichment indicated that four of these genes (\n                    <jats:italic>ASPN, HTRA1, LUM, OGN<\/jats:italic>\n                    ) significantly perturbed pathways related to the regulation of inflammatory response. Immune profiling revealed increased infiltration of fibroblasts and plasma cells in ICM. Molecular docking identified the compound LDN\u2010193189 as a potential lead molecule with high predicted binding affinity (binding energy &lt; \u22129\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) for\n                    <jats:italic>ASPN, LUM<\/jats:italic>\n                    , and\n                    <jats:italic>OGN<\/jats:italic>\n                    . Through multi\u2010omics integration and computational biology, this study systematically delineates a fibroblast\u2010centric molecular network involving key hub genes and an altered immune microenvironment in ICM and computationally proposes a potential therapeutic candidate. These findings provide a crucial computational foundation and experimental direction for understanding ICM pathology and developing novel therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70329","type":"journal-article","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T06:28:54Z","timestamp":1780727334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Single\u2010Cell and Machine Learning Analysis Identifies Fibroblast\u2010Associated Hub Genes and Potential Therapeutics in Ischemic Cardiomyopathy"],"prefix":"10.1111","volume":"107","author":[{"given":"Gaoxiu","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Cardiology Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanming","family":"Zhang","sequence":"additional","affiliation":[{"name":"NO.984 Hospital of the PLA Joint Logistics Support Force  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12968"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2014.83"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-021-10136-3"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7493-1_12"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07393-7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2010.12.093"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02561-8"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12235"},{"issue":"47","key":"e_1_2_11_10_1","first-page":"1916","article-title":"The Role of Oxidative Stress in Heart Failure","volume":"156","author":"G\u00e1l R.","year":"2015","journal-title":"Orvosi Hetilap"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1607355"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.21037\/cdt-21-293"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.604397"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2025.05.002"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2020.118703"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvw201"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2025.01.002"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/6627144"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00028-6"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-025-04546-5"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.curpro.2025.100055"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.039262"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1668627"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14030309"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1108836"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.4291"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28421-6"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-45651-9"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101149"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr312"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.patter.2022.100434"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.125.074959"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.2174\/157016109789043856"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-024-00534-1"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01249-5"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlac057"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11091822"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306565"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001123"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.304599"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2024.11.001"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-244962"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2022.12.002"},{"issue":"2","key":"e_1_2_11_44_1","first-page":"303","article-title":"Asporin Is a Potential Promising Biomarker for Common Heart Failure","volume":"40","author":"Zhang K.","year":"2021","journal-title":"C. Biology"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4550"},{"issue":"4","key":"e_1_2_11_46_1","first-page":"3840","article-title":"p27kip1 Haploinsufficiency Preserves Myocardial Function in the Early Stages of Myocardial Infarction via Atg5\u2010Mediated Autophagy Flux Restoration","volume":"20","author":"Zhou N.","year":"2019","journal-title":"Molecular Medicine Reports"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70329","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cbdd.70329","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70329","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:14:45Z","timestamp":1782483285000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.70329"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1111\/cbdd.70329"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.70329","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"value":"1747-0277","type":"print"},{"value":"1747-0285","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"2026-01-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70329"}}