{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:39:32Z","timestamp":1785487172416,"version":"3.56.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF). In this study, we aimed to explore potential autophagy-related biomarkers associated with DCM with HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The GSE17800 dataset was downloaded from GEO, and differentially expressed genes (DEGs) were identified. Autophagy-related DEGs (AR-DEGs) were obtained by merging DEGs with autophagy-related genes (ARGs) from HADb and HAMdb databases. Gene function enrichment analysis was performed using GO and KEGG. Hub genes were identified via protein-protein interaction (PPI) network analysis, with their expression and diagnostic values validated using the GSE21610 dataset. A doxorubicin (DOX)-induced cardiomyocyte injury model was established to evaluate hub gene expression\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies. Potential therapeutic small molecules targeting hub genes were screened via L1000FWD, and their binding affinity to targets was assessed by molecular docking.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the GSE17800 dataset, a total of 45 AR-DEGs were identified by intersecting with ARGs from HADb and HAMdb. Through PPI network analysis, 7 hub genes were extracted: CDKN1A, CTSD, DDIT3, EP300, FN1, PKM, and SOD2. Further validation using the GSE21610 dataset showed that receiver operating characteristic (ROC) curve analysis confirmed CTSD and SOD2 had high diagnostic value for DCM with HF. Moreover, in both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      DOX-induced cardiomyocyte injury models, DOX treatment resulted in upregulated CTSD expression and downregulated SOD2 expression. Additionally, small molecules targeting CTSD and SOD2 (e.g., QL-XII-47 and tipifarnib-P2) were identified as potential therapeutic candidates for DCM with HF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides novel evidence that CTSD and SOD2 potently contribute to autophagy regulation in DCM with HF. These findings highlight their diagnostic potential for DCM with HF and lay a foundation for exploring targeted small-molecule therapies (e.g., QL-XII-47, tipifarnib-P2) to improve the disease's clinical management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2025.1692768","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T06:41:40Z","timestamp":1768372900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Bioinformatics analyses reveal the autophagy-related feature biomarkers in dilated cardiomyopathy with heart failure"],"prefix":"10.3389","volume":"12","author":[{"given":"Jiayu","family":"Ren","sequence":"first","affiliation":[{"name":"The Institute of Heart and Vascular Diseases, Second Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]},{"name":"Department of Physiology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Second Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"The Institute of Heart and Vascular Diseases, Second Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"The Institute of Heart and Vascular Diseases, Second Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"The Institute of Heart and Vascular Diseases, Second Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"B1","volume-title":"Dilated Cardiomyopathy","author":"Mahmaljy","year":"2022"},{"key":"B2","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/S0140-6736(23)01241-2","article-title":"Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches","volume":"402","author":"Heymans","year":"2023","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1146\/annurev-med-052422-020535","article-title":"Genetics of dilated cardiomyopathy","volume":"75","author":"Eldemire","year":"2024","journal-title":"Annu Rev Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"760515","DOI":"10.3389\/fcell.2021.760515","article-title":"Circular RNA expression for dilated cardiomyopathy in hearts and pluripotent stem cell-derived cardiomyocytes","volume":"9","author":"Zhang","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"81","DOI":"10.7150\/ijbs.28304","article-title":"G protein-coupled estrogen receptor 1 inhibits angiotensin II-induced cardiomyocyte hypertrophy via the regulation of PI3K-Akt-mTOR signalling and autophagy","volume":"15","author":"Pei","year":"2019","journal-title":"Int J Biol Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"152765","DOI":"10.1016\/j.phymed.2018.11.025","article-title":"Allicin attenuates pathological cardiac hypertrophy by inhibiting autophagy via activation of PI3K\/Akt\/mTOR and MAPK\/ERK\/mTOR signaling pathways","volume":"58","author":"Ba","year":"2019","journal-title":"Phytomedicine"},{"key":"B7","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1007\/s12012-021-09667-w","article-title":"MicroRNA-17-5p promotes cardiac hypertrophy by targeting Mfn2 to inhibit autophagy","volume":"21","author":"Xu","year":"2021","journal-title":"Cardiovasc Toxicol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"116748","DOI":"10.1016\/j.lfs.2019.116748","article-title":"Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K\/AKT\/mTOR pathway","volume":"233","author":"Guan","year":"2019","journal-title":"Life Sci"},{"key":"B9","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13321-018-0289-4","article-title":"HAMdb: a database of human autophagy modulators with specific pathway and disease information","volume":"10","author":"Wang","year":"2018","journal-title":"J Cheminform"},{"key":"B10","doi-asserted-by":"publisher","first-page":"15030","DOI":"10.1038\/s41598-022-19027-5","article-title":"Machine learning and bioinformatics to identify 8 autophagy-related biomarkers and construct gene regulatory networks in dilated cardiomyopathy","volume":"12","author":"Zhang","year":"2022","journal-title":"Sci Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID: database for annotation, visualization, and integrated discovery","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"D1049","DOI":"10.1093\/nar\/gku1179","article-title":"Gene ontology consortium: going forward","volume":"43","author":"Gene Ontology","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"3488","DOI":"10.1038\/s41598-023-30666-0","article-title":"Identification and verification of feature biomarkers associated in heart failure by bioinformatics analysis","volume":"13","author":"Yu","year":"2023","journal-title":"Sci Rep"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1097\/JTO.0b013e3181ec173d","article-title":"Receiver operating characteristic curve in diagnostic test assessment","volume":"5","author":"Mandrekar","year":"2010","journal-title":"J Thorac Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"101523","DOI":"10.1016\/j.redox.2020.101523","article-title":"NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy","volume":"34","author":"Zeng","year":"2020","journal-title":"Redox Biol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/s41419-022-05460-x","article-title":"FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM","volume":"13","author":"Bi","year":"2022","journal-title":"Cell Death Dis"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.3390\/antiox12091720","article-title":"PGC-1alpha agonist rescues doxorubicin-induced cardiomyopathy by mitigating the oxidative stress and necroptosis","volume":"12","author":"Shipra","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12951-022-01284-1","article-title":"The effects of extracellular vesicles derived from Kruppel-Like factor 2 overexpressing endothelial cells on the regulation of cardiac inflammation in the dilated cardiomyopathy","volume":"20","author":"Zhang","year":"2022","journal-title":"J Nanobiotechnology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/s00018-024-05395-w","article-title":"SGK3 deficiency in macrophages suppresses angiotensin II-induced cardiac remodeling via regulating Ndufa13-mediated mitochondrial oxidative stress","volume":"81","author":"Ren","year":"2024","journal-title":"Cell Mol Life Sci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"934899","DOI":"10.3389\/fphys.2022.934899","article-title":"I-kappaB kinase-epsilon deficiency improves doxorubicin-induced dilated cardiomyopathy by inhibiting the NF-kappaB pathway","volume":"13","author":"Liu","year":"2022","journal-title":"Front Physiol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1093\/bioinformatics\/bty060","article-title":"L1000FWD: fireworks visualization of drug-induced transcriptomic signatures","volume":"34","author":"Wang","year":"2018","journal-title":"Bioinformatics"},{"key":"B23","doi-asserted-by":"publisher","first-page":"W159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e22982","DOI":"10.1096\/fj.202202079RR","article-title":"TRPA1 deficiency aggravates dilated cardiomyopathy by promoting S100A8 expression to induce M1 macrophage polarization in rats","volume":"37","author":"Wang","year":"2023","journal-title":"FASEB J"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3921","DOI":"10.1002\/ptr.8236","article-title":"Genistein alleviates doxorubicin-induced cardiomyocyte autophagy and apoptosis via ERK\/STAT3\/c-Myc signaling pathway in rat model","volume":"38","author":"Wu","year":"2024","journal-title":"Phytother Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.3892\/mmr.2015.4665","article-title":"Resveratrol protects cardiomyocytes from doxorubicin-induced apoptosis through the AMPK\/P53 pathway","volume":"13","author":"Liu","year":"2016","journal-title":"Mol Med Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41374-019-0349-z","article-title":"TRPV2 channel as a possible drug target for the treatment of heart failure","volume":"100","author":"Iwata","year":"2020","journal-title":"Lab Invest"},{"key":"B28","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1080\/15548627.2020.1741202","article-title":"The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis","volume":"17","author":"Pi","year":"2021","journal-title":"Autophagy"},{"key":"B29","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1007\/s11626-019-00417-5","article-title":"MicroRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy","volume":"56","author":"Jin","year":"2020","journal-title":"In Vitro Cell Dev Biol Anim"},{"key":"B30","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s12872-020-01365-9","article-title":"Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy","volume":"20","author":"Jin","year":"2020","journal-title":"BMC Cardiovasc Disord"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.3390\/jcm8101519","article-title":"Autophagy and inflammasome activation in dilated cardiomyopathy","volume":"8","author":"Caragnano","year":"2019","journal-title":"J Clin Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"903","DOI":"10.4161\/auto.19653","article-title":"MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB","volume":"8","author":"Martina","year":"2012","journal-title":"Autophagy"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB","volume":"31","author":"Settembre","year":"2012","journal-title":"EMBO J"},{"key":"B34","doi-asserted-by":"publisher","first-page":"4101","DOI":"10.1111\/jcmm.17455","article-title":"Transcriptome analysis uncovers the autophagy-mediated regulatory patterns of the immune microenvironment in dilated cardiomyopathy","volume":"26","author":"Sun","year":"2022","journal-title":"J Cell Mol Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0215818","DOI":"10.1371\/journal.pone.0215818","article-title":"The altered expression of autophagy-related genes participates in heart failure: NRBP2 and CALCOCO2 are associated with left ventricular dysfunction parameters in human dilated cardiomyopathy","volume":"14","author":"Gil-Cayuela","year":"2019","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"747803","DOI":"10.3389\/fcvm.2021.747803","article-title":"An robust rank aggregation and least absolute shrinkage and selection operator analysis of novel gene signatures in dilated cardiomyopathy","volume":"8","author":"Ma","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"30","DOI":"10.20517\/jca.2022.14","article-title":"Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype","volume":"2","author":"Rouhi","year":"2022","journal-title":"J Cardiovasc Aging"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e14054","DOI":"10.1111\/eci.14054","article-title":"Heart failure in patients is associated with downregulation of mitochondrial quality control genes","volume":"53","author":"Svagusa","year":"2023","journal-title":"Eur J Clin Invest"},{"key":"B39","doi-asserted-by":"publisher","first-page":"8925420","DOI":"10.1155\/2020\/8925420","article-title":"Integrated analysis of hub genes and miRNAs in dilated cardiomyopathy","volume":"2020","author":"Huang","year":"2020","journal-title":"Biomed Res Int"},{"key":"B40","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1152\/physiolgenomics.00111.2018","article-title":"Correlation of gene expression and clinical parameters identifies a set of genes reflecting LV systolic dysfunction and morphological alterations","volume":"51","author":"Witt","year":"2019","journal-title":"Physiol Genomics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.jacc.2021.11.059","article-title":"Impact of autophagy on prognosis of patients with dilated cardiomyopathy","volume":"79","author":"Kanamori","year":"2022","journal-title":"J Am Coll Cardiol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e004044","DOI":"10.1161\/CIRCHEARTFAILURE.117.004044","article-title":"Myocardial upregulation of Cathepsin D by ischemic heart disease promotes autophagic flux and protects against cardiac remodeling and heart failure","volume":"10","author":"Wu","year":"2017","journal-title":"Circ Heart Fail"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2102","DOI":"10.1002\/ejhf.1674","article-title":"The role of Cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach","volume":"22","author":"Hoes","year":"2020","journal-title":"Eur J Heart Fail"},{"key":"B44","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1136\/jmedgenet-2019-106330","article-title":"Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy","volume":"57","author":"Almomani","year":"2020","journal-title":"J Med Genet"},{"key":"B45","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.jjcc.2016.05.019","article-title":"EGCG, a green tea catechin, attenuates the progression of heart failure induced by the heart\/muscle-specific deletion of MnSOD in mice","volume":"69","author":"Oyama","year":"2017","journal-title":"J Cardiol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1136\/jmg.2004.019588","article-title":"The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis","volume":"41","author":"Valenti","year":"2004","journal-title":"J Med Genet"},{"key":"B47","doi-asserted-by":"publisher","first-page":"24117","DOI":"10.18632\/aging.202283","article-title":"Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner","volume":"12","author":"Barcena","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1161\/CIRCRESAHA.123.324110","article-title":"Tipifarnib reduces extracellular vesicles and protects from heart failure","volume":"135","author":"Mallaredy","year":"2024","journal-title":"Circ Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.matbio.2022.08.010","article-title":"Loss of BTK ameliorates the pathological cardiac fibrosis and dysfunction","volume":"112","author":"Wang","year":"2022","journal-title":"Matrix Biol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2939","DOI":"10.1111\/jth.15899","article-title":"The Btk inhibitor AB-95-LH34 potently inhibits atherosclerotic plaque-induced thrombus formation and platelet procoagulant activity","volume":"20","author":"Smith","year":"2022","journal-title":"J Thromb Haemost"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1182\/blood-2017-09-808808","article-title":"Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans","volume":"131","author":"Busygina","year":"2018","journal-title":"Blood"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2025.1692768\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T06:54:10Z","timestamp":1771916050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2025.1692768\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,14]]},"references-count":51,"alternative-id":["10.3389\/fcvm.2025.1692768"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2025.1692768","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,14]]},"article-number":"1692768"}}