{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:06:18Z","timestamp":1773335178810,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"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>Background<\/jats:title>\n                    <jats:p>As the primary pathological basis for cardiovascular diseases, atherosclerosis (AS) arises from pathogenesis closely linked to dysregulated cholesterol metabolism and ferroptosis. This study seeks to develop an AS diagnostic model and identify potential biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      AS-related transcriptomic datasets were obtained from the GEO database. Differentially expressed cholesterol metabolism- and ferroptosis-related genes (DE-CM-FRGs) were screened by integrating WGCNA module genes, AS-related differentially expressed genes, cholesterol metabolism-related genes, and ferroptosis-related genes. Consensus clustering was performed to subtype AS patients. Hub genes were refined using three machine learning algorithms: Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE) and Boruta. A logistic regression diagnostic model based on filtered genes was established and evaluated with ROC curves. A nomogram was constructed and evaluated through calibration, decision, and impact curves, followed by building a diagnostic gene-based regulatory network. Single-cell RNA sequencing analyzed HMOX1-expressing cells.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , HMOX1 knockdown effects on proliferation, ROS, MDA, iron content, and mRNA expression of SLC7A11, GPX4, and ACSL4 were assessed in ox-LDL-induced THP-1 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The identified five core feature genes (CD36, DPP4, HMOX1, IL1B, NFIL3) exhibited robust diagnostic relevance and auxiliary discriminant value across both training and validation sets. The diagnostic model based on these five genes exhibited strong discriminatory ability in both sets. Regulatory network analysis revealed interactions between the diagnostic genes and transcription factors, miRNAs, and compounds. HMOX1 knockdown suppressed ox-LDL-induced THP-1 cell proliferation, lowered intracellular ROS, MDA, and iron levels, upregulated GPX4 and SLC7A11 expression, and downregulated ACSL4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>By systematically identifying key genes in AS-associated cholesterol metabolism and ferroptosis, this study constructs a robust diagnostic model and identifies potential biomarkers and therapeutic targets for AS diagnosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1715946","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T05:28:39Z","timestamp":1773293319000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Establishing an atherosclerosis diagnostic model based on WGCNA and machine learning algorithms with key genes in cholesterol metabolism and ferroptosis, and revealing the regulatory role of HMOX1 in cellular ferroptosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Zengguang","family":"Fan","sequence":"first","affiliation":[{"name":"Cardiovascular Medicine Department, Affiliated Hospital of Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caihui","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiwen","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zijian","family":"Hong","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianming","family":"Zhong","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Yuan","sequence":"additional","affiliation":[{"name":"Endocrine Department, Affiliated Hospital of Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7910","DOI":"10.3390\/ijms24097910","article-title":"Atherosclerosis and inflammation: insights from the theory of general pathological processes","volume":"24","author":"Gusev","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jacc.2021.10.035","article-title":"Coronary atherosclerotic plaque regression: JACC state-of-the-art review","volume":"79","author":"Dawson","year":"2022","journal-title":"J Am Coll Cardiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1016\/j.clinthera.2023.09.020","article-title":"Global trends in atherosclerotic cardiovascular disease","volume":"45","author":"Nedkoff","year":"2023","journal-title":"Clin Ther"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3346","DOI":"10.3390\/ijms23063346","article-title":"Pathophysiology of atherosclerosis","volume":"23","author":"Jebari-Benslaiman","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.3390\/ijms23031332","article-title":"Cholesterol transport dysfunction and its involvement in atherogenesis","volume":"23","author":"Poznyak","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1093\/cvr\/cvab076","article-title":"Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis","volume":"118","author":"Liu","year":"2022","journal-title":"Cardiovasc Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1177\/10742484211023632","article-title":"Targeting the cholesterol paradigm in the risk reduction for atherosclerotic cardiovascular disease: does the mechanism of action of pharmacotherapy matter for clinical outcomes?","volume":"26","author":"Zhou","year":"2021","journal-title":"J Cardiovasc Pharmacol Ther"},{"key":"B8","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41569-024-01039-5","article-title":"The LDL cumulative exposure hypothesis: evidence and practical applications","volume":"21","author":"Ference","year":"2024","journal-title":"Nat Rev Cardiol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"100190","DOI":"10.1016\/j.ajpc.2021.100190","article-title":"Discordantly normal ApoB relative to elevated LDL-C in persons with metabolic disorders: a marker of atherogenic heterogeneity","volume":"7","author":"Razavi","year":"2021","journal-title":"Am J Prev Cardiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"313","DOI":"10.3390\/jcm11020313","article-title":"Discordance between LDL-C and apolipoprotein B levels and its association with renal dysfunction: insights from a population-based study","volume":"11","author":"Mazidi","year":"2022","journal-title":"J Clin Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"151058","DOI":"10.1016\/j.ejcb.2019.151058","article-title":"Mitochondria regulation in ferroptosis","volume":"99","author":"Wang","year":"2020","journal-title":"Eur J Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"117892","DOI":"10.1016\/j.jep.2024.117892","article-title":"Gualou-Xiebai herb pair ameliorate atherosclerosis in HFD-induced ApoE(-\/-) mice and inhibit the ox-LDL-induced injury of HUVECs by regulating the Nrf2-mediated ferroptosis","volume":"326","author":"Zhu","year":"2024","journal-title":"J Ethnopharmacol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.freeradbiomed.2020.07.026","article-title":"Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell","volume":"160","author":"Bai","year":"2020","journal-title":"Free Radic Biol Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e22992","DOI":"10.1096\/fj.202300083R","article-title":"Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2\/GPX4 pathway","volume":"37","author":"Lv","year":"2023","journal-title":"FASEB J"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1084531","DOI":"10.3389\/fimmu.2023.1084531","article-title":"Identification and validation of immune and oxidative stress-related diagnostic markers for diabetic nephropathy by WGCNA and machine learning","volume":"14","author":"Xu","year":"2023","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1335112","DOI":"10.3389\/fimmu.2024.1335112","article-title":"Integrative analysis identifies oxidative stress biomarkers in non-alcoholic fatty liver disease via machine learning and weighted gene co-expression network analysis","volume":"15","author":"Wang","year":"2024","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1030198","DOI":"10.3389\/fimmu.2023.1030198","article-title":"Single-cell RNA and transcriptome sequencing profiles identify immune-associated key genes in the development of diabetic kidney disease","volume":"14","author":"Zhang","year":"2023","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"871008","DOI":"10.3389\/fimmu.2022.871008","article-title":"Bioinformatics-Led discovery of osteoarthritis biomarkers and inflammatory infiltrates","volume":"13","author":"Hu","year":"2022","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"154621","DOI":"10.1016\/j.prp.2023.154621","article-title":"Comprehensive analyses of genome-wide methylation and RNA epigenetics identify prognostic biomarkers, regulating the tumor immune microenvironment in lung adenocarcinoma","volume":"248","author":"Liu","year":"2023","journal-title":"Pathol Res Pract"},{"key":"B20","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1007\/s11033-024-09406-8","article-title":"SIRT1 And ZNF350 as novel biomarkers for osteoporosis: a bioinformatics analysis and experimental validation","volume":"51","author":"Zhu","year":"2024","journal-title":"Mol Biol Rep"},{"key":"B21","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"Clusterprofiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"103327","DOI":"10.4254\/wjh.v17.i3.103327","article-title":"Immune cells in metabolic associated fatty liver disease: global trends and hotspots (2004\u20132024)","volume":"17","author":"Qi","year":"2025","journal-title":"World J Hepatol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1007\/s40618-023-02262-6","article-title":"Single-cell and bulk RNA sequencing reveal heterogeneity and diagnostic markers in papillary thyroid carcinoma lymph-node metastasis","volume":"47","author":"Lu","year":"2024","journal-title":"J Endocrinol Invest"},{"key":"B24","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s12957-024-03523-1","article-title":"Early identification of hepatocellular carcinoma patients at high-risk of recurrence using the ADV score: a multicenter retrospective study","volume":"22","author":"Cao","year":"2024","journal-title":"World J Surg Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1186\/s12884-025-07669-y","article-title":"The prognostic nutritional index is associated with preeclampsia in twin pregnancies","volume":"25","author":"Han","year":"2025","journal-title":"BMC Pregnancy Childbirth"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3709","DOI":"10.1038\/s41598-024-54135-4","article-title":"scRNA-seq revealed high stemness epithelial malignant cell clusters and prognostic models of lung adenocarcinoma","volume":"14","author":"Lin","year":"2024","journal-title":"Sci Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e0296034","DOI":"10.1371\/journal.pone.0296034","article-title":"Explore the shared molecular mechanism between dermatomyositis and nasopharyngeal cancer by bioinformatic analysis","volume":"19","author":"Zhong","year":"2024","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"547","DOI":"10.2147\/CMAR.S462951","article-title":"Application of chest CT imaging feature model in distinguishing squamous cell carcinoma and adenocarcinoma of the lung","volume":"16","author":"Liu","year":"2024","journal-title":"Cancer Manag Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep"},{"key":"B30","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.jvssci.2021.11.002","article-title":"Vascular smooth muscle cell phenotype switching in carotid atherosclerosis","volume":"3","author":"Chou","year":"2022","journal-title":"JVS Vasc Sci"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e124574","DOI":"10.1172\/jci.insight.124574","article-title":"Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression","volume":"4","author":"Lin","year":"2019","journal-title":"JCI Insight"},{"key":"B32","doi-asserted-by":"publisher","first-page":"18949","DOI":"10.1038\/s41598-025-03757-3","article-title":"The role of HMOX1-mediated ferroptosis in blue light-induced damage to retinal pigment epithelium","volume":"15","author":"Ji","year":"2025","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","first-page":"102987","DOI":"10.1016\/j.redox.2023.102987","article-title":"MCL Attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1\/NRF2 interaction","volume":"69","author":"Luo","year":"2024","journal-title":"Redox Biol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/s41419-024-07166-8","article-title":"Inflammation in atherosclerosis: pathophysiology and mechanisms","volume":"15","author":"Ajoolabady","year":"2024","journal-title":"Cell Death Dis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"115965","DOI":"10.1016\/j.bcp.2023.115965","article-title":"Is the suppression of CD36 a promising way for atherosclerosis therapy?","volume":"219","author":"Wen","year":"2024","journal-title":"Biochem Pharmacol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1210\/clinem\/dgab078","article-title":"DPP4 Activity, hyperinsulinemia, and atherosclerosis","volume":"106","author":"Love","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1244632","DOI":"10.3389\/fphar.2024.1244632","article-title":"Ateroprotective effects of Plinia cauliflora in. New Zealand rabbits: beyond the lipid-lowering effect","volume":"15","author":"Cestari","year":"2024","journal-title":"Front Pharmacol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"102096","DOI":"10.1016\/j.cpcardiol.2023.102096","article-title":"A potential role of NFIL3 in atherosclerosis","volume":"49","author":"Zeng","year":"2024","journal-title":"Curr Probl Cardiol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.niox.2023.11.005","article-title":"Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation","volume":"142","author":"Zhou","year":"2024","journal-title":"Nitric Oxide"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2672","DOI":"10.1073\/pnas.1821022116","article-title":"Ferroptosis as a target for protection against cardiomyopathy","volume":"116","author":"Fang","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B41","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/s41422-019-0150-y","article-title":"Broken hearts: iron overload, ferroptosis and cardiomyopathy","volume":"29","author":"Conrad","year":"2019","journal-title":"Cell Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1016\/j.devcel.2024.12.011","article-title":"HMOX1-LDHB Interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis","volume":"60","author":"Peng","year":"2025","journal-title":"Dev Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1093\/cvr\/cvaf013","article-title":"Circular RNAs increase during vascular cell differentiation and are biomarkers for vascular disease","volume":"121","author":"Northoff","year":"2025","journal-title":"Cardiovasc Res"},{"key":"B44","doi-asserted-by":"publisher","first-page":"318","DOI":"10.3390\/diagnostics11020318","article-title":"Circulating miRNAs are associated with the systemic extent of atherosclerosis: novel observations for miR-27b and miR-146","volume":"11","author":"Pereira-da-Silva","year":"2021","journal-title":"Diagnostics (Basel)"},{"key":"B45","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1536\/ihj.24-150","article-title":"Effects of LncRNA MYOSLID and MiR-29c-3p on the proliferation and migration of angiotensin II-induced vascular smooth muscle cells","volume":"66","author":"Ye","year":"2025","journal-title":"Int Heart J"},{"key":"B46","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12964-022-00828-0","article-title":"Endothelial colony-forming cell-derived exosomal miR-21-5p regulates autophagic flux to promote vascular endothelial repair by inhibiting SIPL1A2 in atherosclerosis","volume":"20","author":"Ke","year":"2022","journal-title":"Cell Commun Signal"},{"key":"B47","doi-asserted-by":"publisher","first-page":"153858","DOI":"10.1016\/j.prp.2022.153858","article-title":"MiRNA-205-5p regulates the ERBB4\/AKT signaling pathway to inhibit the proliferation and migration of HAVSMCs induced by ox-LDL","volume":"233","author":"Huang","year":"2022","journal-title":"Pathol Res Pract"},{"key":"B48","doi-asserted-by":"publisher","first-page":"106622","DOI":"10.1016\/j.jstrokecerebrovasdis.2022.106622","article-title":"LncRNA KCNQ1OT1 participates in ox-LDL-induced proliferation\/apoptosis imbalance in vascular smooth muscle cells by regulating the MiR-196a-5p\/FOXO1 axis","volume":"31","author":"Li","year":"2022","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"B49","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.atherosclerosis.2013.08.002","article-title":"Docosahexaenoic acid (DHA)-induced heme oxygenase-1 attenuates cytotoxic effects of DHA in vascular smooth muscle cells","volume":"230","author":"Stulnig","year":"2013","journal-title":"Atherosclerosis"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1161\/ATVBAHA.107.142638","article-title":"Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors","volume":"27","author":"Kronke","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/S0140-6736(22)01602-6","article-title":"Autoimmune diseases and atherothrombotic risk","volume":"400","author":"Ridker","year":"2022","journal-title":"Lancet"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1715946\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T05:28:40Z","timestamp":1773293320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1715946\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":51,"alternative-id":["10.3389\/fcvm.2026.1715946"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1715946","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]},"article-number":"1715946"}}