{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T08:18:59Z","timestamp":1788164339816,"version":"build-2803163510"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":19,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the Capital\u2019s Funds for Health Improvement and Research","award":["2026-2-4164"],"award-info":[{"award-number":["2026-2-4164"]}]},{"name":"the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences","award":["CI2026A00907"],"award-info":[{"award-number":["CI2026A00907"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>To elucidate the molecular characteristics of synergistic interactions across the clinical stages of coronary heart disease (CHD)\u2014specifically stable angina pectoris (SAP), unstable angina pectoris (UAP), and acute myocardial infarction (AMI)\u2014through integrated metabolomic and proteomic analyses. Based on a cohort including SAP, UAP, AMI, and healthy controls, metabolomic and proteomic analyses were performed to identify differentially expressed molecules, followed by KEGG pathway enrichment analysis. Pathways co-enriched across both omics platforms were selected to construct metabolite-protein interaction networks. The number of pathways co-enriched in both metabolomic and proteomic analyses increased markedly with disease stage. Only two pathways (histidine metabolism and arginine and proline metabolism) were identified in the SAP stage; this number increased to five in the UAP stage (including ferroptosis and efferocytosis) and expanded to 25 in the AMI stage, encompassing three major functional modules: immune inflammation, metabolic reprogramming, and cell signaling. The core network exhibited a stepwise increase in connectivity, shifting from a sparse structure in the SAP stage to a highly interconnected architecture in the AMI stage, with L-glutamate and KNG1 identified as the central hubs in this cross-sectional network. In addition, CNDP1 exhibited a stage-dependent functional transition, shifting from downregulation in SAP to upregulation in AMI. In this cross-sectional analysis, metabolic dysregulation and immune activation exhibited stepwise increases in interconnectivity across the SAP, UAP, and AMI groups, with the most extensive crosstalk observed in the AMI stage\u2014a network configuration consistent with a tightly coupled \u201cmolecular storm\u201d. These findings provide novel insights into stage-associated molecular signatures of CHD and identify candidate hub molecules for stage-oriented therapeutic investigation.<\/jats:p>","DOI":"10.1038\/s41598-026-66673-0","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T13:46:12Z","timestamp":1786542372000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative multi-omics analysis of metabolite\u2013protein interaction networks across different stages of coronary heart disease"],"prefix":"10.1038","volume":"16","author":[{"given":"Xilun","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxiaoxue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yishuang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meili","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinsheng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"66673_CR1","doi-asserted-by":"crossref","unstructured":"Tsao, C. W. et al. Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association. Circulation 147, e93\u2013e621 .","DOI":"10.1161\/CIR.0000000000001137"},{"key":"66673_CR2","doi-asserted-by":"crossref","unstructured":"Libby, P., Pasterkamp, G., Crea, F. & Jang, I. K. Reassessing the Mechanisms of Acute Coronary Syndromes. Circ Res 124, 150\u2013160 .","DOI":"10.1161\/CIRCRESAHA.118.311098"},{"key":"66673_CR3","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.jacc.2023.04.003","volume":"82","author":"SS Virani","year":"2023","unstructured":"Virani, S. S. et al. AHA\/ACC\/ACCP\/ASPC\/NLA\/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association\/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 82, 833\u2013955 (2023).","journal-title":"J. Am. Coll. Cardiol."},{"key":"66673_CR4","doi-asserted-by":"crossref","unstructured":"Libby, P. The changing landscape of atherosclerosis. Nature 592, 524\u2013533 .","DOI":"10.1038\/s41586-021-03392-8"},{"key":"66673_CR5","doi-asserted-by":"crossref","unstructured":"Karczewski, K. J. & Snyder, M. P. Integrative omics for health and disease. Nat Rev. Genet 19, 299\u2013310 .","DOI":"10.1038\/nrg.2018.4"},{"key":"66673_CR6","doi-asserted-by":"crossref","unstructured":"Jang, C., Chen, L. & Rabinowitz, J. D. Metabolomics and Isotope Tracing. Cell 173, 822\u2013837 .","DOI":"10.1016\/j.cell.2018.03.055"},{"key":"66673_CR7","doi-asserted-by":"crossref","unstructured":"Xiao, Y. et al. Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer. Clin Cancer Res 25, 5002\u20135014 .","DOI":"10.1158\/1078-0432.CCR-18-3524"},{"key":"66673_CR8","doi-asserted-by":"crossref","unstructured":"Sch\u00fcssler-Fiorenza Rose, S. M. et al. A longitudinal big data approach for precision health. Nat Med 25, 792\u2013804 .","DOI":"10.1038\/s41591-019-0414-6"},{"key":"66673_CR9","unstructured":"Johnson, E. C. B. et al. Large-scale proteomic analysis of Alzheimer\u2019s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med 26, 769\u2013780 ."},{"key":"66673_CR10","doi-asserted-by":"crossref","unstructured":"McGarrah, R. W., Crown, S. B., Zhang, G. F., Shah, S. H. & Newgard, C. B. Cardiovascular Metabolomics. Circ Res 122, 1238\u20131258 .","DOI":"10.1161\/CIRCRESAHA.117.311002"},{"key":"66673_CR11","doi-asserted-by":"crossref","unstructured":"Nurmohamed, N. S. et al. Proteomics and lipidomics in atherosclerotic cardiovascular disease risk prediction. Eur Heart J 44, 1594\u20131607 .","DOI":"10.1093\/eurheartj\/ehad161"},{"key":"66673_CR12","doi-asserted-by":"crossref","unstructured":"Thygesen, K. et al. Fourth Universal Definition of Myocardial Infarction (2018). J Am. Coll. Cardiol 72, 2231\u20132264 .","DOI":"10.1016\/j.jacc.2018.08.1038"},{"key":"66673_CR13","unstructured":"Vrints, C. et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J 45, 3415\u20133537 ."},{"key":"66673_CR14","doi-asserted-by":"crossref","unstructured":"Braunwald, E. Unstable angina. A classification. Circulation 80, 410\u2013414 .","DOI":"10.1161\/01.CIR.80.2.410"},{"key":"66673_CR15","doi-asserted-by":"crossref","unstructured":"Kanehisa, M., Furumichi, M., Tanabe, M., Sato, Y. & Morishima, K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45, D353\u2013d361 .","DOI":"10.1093\/nar\/gkw1092"},{"key":"66673_CR16","doi-asserted-by":"crossref","unstructured":"Engstr\u00f6m, G. et al. Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 105, 2632\u20132637 .","DOI":"10.1161\/01.CIR.0000017327.69909.FF"},{"key":"66673_CR17","doi-asserted-by":"crossref","unstructured":"Shu, L. X., Cao, L. L., Guo, X., Wang, Z. B. & Wang, S. Z. Mechanism of efferocytosis in atherosclerosis. J Mol. Med. (Berl) 102, 831\u2013840 .","DOI":"10.1007\/s00109-024-02439-3"},{"key":"66673_CR18","doi-asserted-by":"crossref","unstructured":"Xu, X. et al. The mechanisms of ferroptosis and its role in atherosclerosis. Biomed Pharmacother 171, 116112 .","DOI":"10.1016\/j.biopha.2023.116112"},{"key":"66673_CR19","doi-asserted-by":"crossref","unstructured":"Wang, X., Yang, G., Li, J., Meng, C. & Xue, Z. Dynamic molecular signatures of acute myocardial infarction based on transcriptomics and metabolomics. Sci Rep 14, 10175 .","DOI":"10.1038\/s41598-024-60945-3"},{"key":"66673_CR20","doi-asserted-by":"crossref","unstructured":"Lu, R. et al. Plasma Metabolic Profiling and Multiclass Diagnostic Model Development for Stable Angina Pectoris and Acute Myocardial Infarction. ACS Omega 9, 16322\u201316333 .","DOI":"10.1021\/acsomega.3c10474"},{"key":"66673_CR21","doi-asserted-by":"crossref","unstructured":"Hipkiss, A. R. Carnosine and its possible roles in nutrition and health. Adv Food Nutr. Res 57, 87\u2013154 .","DOI":"10.1016\/S1043-4526(09)57003-9"},{"key":"66673_CR22","doi-asserted-by":"crossref","unstructured":"Schm\u00f6hl, F. et al. CNDP1 knockout in zebrafish alters the amino acid metabolism, restrains weight gain, but does not protect from diabetic complications. Cell Mol. Life Sci 76, 4551\u20134568 .","DOI":"10.1007\/s00018-019-03127-z"},{"key":"66673_CR23","doi-asserted-by":"crossref","unstructured":"Liu, C. et al. THBS1 in macrophage-derived exosomes exacerbates cerebral ischemia-reperfusion injury by inducing ferroptosis in endothelial cells. J Neuroinflammation 22, 48 .","DOI":"10.1186\/s12974-025-03382-x"},{"key":"66673_CR24","doi-asserted-by":"crossref","unstructured":"Wang, D. et al. The molecular mechanisms of cuproptosis and its relevance to cardiovascular disease. Biomed Pharmacother 163, 114830 .","DOI":"10.1016\/j.biopha.2023.114830"},{"key":"66673_CR25","doi-asserted-by":"crossref","unstructured":"Park, S. H., Kang, J. H. & Bae, Y. S. The role and regulation of phospholipase D in metabolic disorders. Adv Biol. Regul 91, 100988 .","DOI":"10.1016\/j.jbior.2023.100988"},{"key":"66673_CR26","doi-asserted-by":"crossref","unstructured":"Cheng, X. et al. Overexpression of Kininogen-1 aggravates oxidative stress and mitochondrial dysfunction in DOX-induced cardiotoxicity. Biochem Biophys. Res. Commun 550, 142\u2013150 .","DOI":"10.1016\/j.bbrc.2021.02.104"},{"key":"66673_CR27","doi-asserted-by":"crossref","unstructured":"Newsholme, P., Diniz, V. L. S., Dodd, G. T. & Cruzat, V. Glutamine metabolism and optimal immune and CNS function. Proc Nutr. Soc 82, 22\u201331 .","DOI":"10.1017\/S0029665122002749"},{"key":"66673_CR28","doi-asserted-by":"crossref","unstructured":"Bajic, V. P. et al. Glutathione Redox Homeostasis and Its Relation to Cardiovascular Disease. Oxid Med. Cell. Longev 5028181. (2019).","DOI":"10.1155\/2019\/5028181"},{"key":"66673_CR29","doi-asserted-by":"crossref","unstructured":"Rochette, L. et al. Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. Int J. Mol. Sci 24.","DOI":"10.3390\/ijms24010449"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-66673-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-66673-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-66673-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T08:06:59Z","timestamp":1788163619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-66673-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["66673"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-66673-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"assertion":[{"value":"1 July 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study complied with the Declaration of Helsinki and obtained ethical approval from the Wangjing Hospital of China Academy of Chinese Medical Sciences (Registration No. WJEC-KT-2022-031-P001).","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"27226"}}