{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:56:25Z","timestamp":1790740585080,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Coronary atherosclerosis (CA) is characterized by profound macrophage heterogeneity that drives plaque progression and vulnerability, yet the precise subpopulations and their niche\u2010specific functions remain incompletely defined. Here, we constructed a single\u2010cell transcriptomic atlas of human CA using dataset GSE131778 and identified six distinct macrophage subpopulations. Among these, the THBS1+ macrophage subset emerged as a terminally differentiated, hypoxia\u2010adaptive population with elevated TGF\u2010\u03b2 signaling and FOSB\u2010driven transcriptional regulation. High\u2010dimensional weighted gene co\u2010expression network analysis revealed 12 transcriptional modules, with module NEW10 serving as a specific molecular signature of THBS1+ macrophages. Cell\u2013cell communication analysis predicted a THBS1\u2010CD36 ligand\u2010receptor interaction potentially contributing to crosstalk between THBS1+ macrophages and lymphatic endothelial cells. Molecular docking and 100\u2010ns molecular dynamics simulations predicted a thermodynamically favorable and conformationally stable interaction between SMS121 and CD36, providing an initial computational rationale for further experimental evaluation. Finally, leveraging the NEW10 module genes, we trained 13 machine learning classifiers to distinguish ACS from sCAD and evaluated their performance in differentiating ruptured from stable plaques; Support Vector Machine with linear kernel and Naive Bayes achieved the highest accuracy in an independent testing cohort, both attaining an AUC of 0.9333. These findings illuminate macrophage heterogeneity and intercellular communication in CA, identify the predicted THBS1\u2010CD36 interaction as a candidate for further mechanistic and pharmacological investigation, and establish a macrophage\u2010derived transcriptional signature for precise risk stratification.<\/jats:p>","DOI":"10.1111\/cbdd.70399","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:09:02Z","timestamp":1790737742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Single\u2010Cell Transcriptomics, Multi\u2010Omics Analyses, and Computational Pharmacology Reveal Macrophage Heterogeneity and the Putative\n                    <scp>THBS1<\/scp>\n                    \u2010\n                    <scp>CD36<\/scp>\n                    Axis in Coronary Atherosclerosis"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1203-4960","authenticated-orcid":false,"given":"Jianpeng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"},{"name":"Department of Cardiology Taizhou Second People's Hospital Affiliated to Yangzhou University  Taizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Liu","sequence":"additional","affiliation":[{"name":"Queen Mary College Jiangxi Medical College, Nanchang University  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4667-4812","authenticated-orcid":false,"given":"Run","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Taizhou Second People's Hospital Affiliated to Yangzhou University  Taizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5203-6668","authenticated-orcid":false,"given":"Rong","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"1","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"9104","DOI":"10.1038\/s41598-024-58689-1","article-title":"SMS121, a New Inhibitor of CD36, Impairs Fatty Acid Uptake and Viability of Acute Myeloid Leukemia","volume":"14","author":"\u00c5backa H.","year":"2024","journal-title":"Scientific Reports"},{"issue":"1","key":"e_1_2_13_3_1","first-page":"24","article-title":"Recent Advances in Single\u2010Cell Analysis of Atherosclerotic Plaque Biology","volume":"9","author":"Adachi Y.","year":"2026","journal-title":"Jma j"},{"issue":"11","key":"e_1_2_13_4_1","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: Single\u2010Cell Regulatory Network Inference and Clustering","volume":"14","author":"Aibar S.","year":"2017","journal-title":"Nature Methods"},{"issue":"10","key":"e_1_2_13_5_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms26104524","article-title":"Tissue\u2010Resident Macrophages in Cardiovascular Diseases: Heterogeneity and Therapeutic Potential","volume":"26","author":"An T.","year":"2025","journal-title":"International Journal of Molecular Sciences"},{"issue":"11","key":"e_1_2_13_6_1","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1161\/ATVBAHA.124.319571","article-title":"Decoding Macrophage Heterogeneity to Unravel Vascular Inflammation as a Path to Precision Medicine","volume":"44","author":"Chelvanambi S.","year":"2024","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"issue":"9","key":"e_1_2_13_7_1","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s42255-019-0102-3","article-title":"Endothelial TGF\u2010\u03b2 Signalling Drives Vascular Inflammation and Atherosclerosis","volume":"1","author":"Chen P. Y.","year":"2019","journal-title":"Nature Metabolism"},{"issue":"31","key":"e_1_2_13_8_1","doi-asserted-by":"crossref","first-page":"28277","DOI":"10.1021\/acsomega.3c02082","article-title":"Molecular Drug Simulation and Experimental Validation of the CD36 Receptor Competitively Binding to Long\u2010Chain Fatty Acids by 7\u2010Ketocholesteryl\u20109\u2010Carboxynonanoate","volume":"8","author":"Fu C.","year":"2023","journal-title":"ACS Omega"},{"issue":"9","key":"e_1_2_13_9_1","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/s41590-018-0179-y","article-title":"PLD3 and PLD4 Are Single\u2010Stranded Acid Exonucleases That Regulate Endosomal Nucleic\u2010Acid Sensing","volume":"19","author":"Gavin A. L.","year":"2018","journal-title":"Nature Immunology"},{"issue":"7","key":"e_1_2_13_10_1","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1093\/emboj\/21.7.1743","article-title":"Balancing the Activation State of the Endothelium via Two Distinct TGF\u2010Beta Type I Receptors","volume":"21","author":"Goumans M. J.","year":"2002","journal-title":"EMBO Journal"},{"issue":"5","key":"e_1_2_13_11_1","doi-asserted-by":"crossref","DOI":"10.1111\/cbdd.70205","article-title":"Identification of New CD36 Antagonists by Structure\u2010Based Virtual Screening","volume":"106","author":"Guerrero\u2010Rodr\u00edguez S. 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E.","year":"2023","journal-title":"Circulation Research"},{"issue":"8","key":"e_1_2_13_37_1","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1038\/s41591-019-0512-5","article-title":"Atheroprotective Roles of Smooth Muscle Cell Phenotypic Modulation and the TCF21 Disease Gene as Revealed by Single\u2010Cell Analysis","volume":"25","author":"Wirka R. C.","year":"2019","journal-title":"Nature Medicine"},{"issue":"1","key":"e_1_2_13_38_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40246-025-00869-9","article-title":"APM+ Macrophages Associated With Plaque Vulnerability via MIF\u2010CD74 Signaling: A Multi\u2010Omics Study","volume":"20","author":"Xu X.","year":"2026","journal-title":"Human Genomics"},{"issue":"8","key":"e_1_2_13_39_1","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.7150\/ijbs.112061","article-title":"Omics\u2010Based Approach Towards Macrophages: New Perspectives of Biology and Function in the Normal and Diseased Heart","volume":"21","author":"Yang C.","year":"2025","journal-title":"International Journal of Biological Sciences"},{"key":"e_1_2_13_40_1","doi-asserted-by":"crossref","first-page":"809","DOI":"10.5551\/jat.65991","article-title":"A Single\u2010Cell Analysis Reveals Macrophage Heterogeneity Driving Plaque Vulnerability in Coronary and Carotid Arteries","volume":"33","author":"Yoshida T.","year":"2026","journal-title":"Journal of Atherosclerosis and Thrombosis"},{"issue":"5","key":"e_1_2_13_41_1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu G.","year":"2012","journal-title":"OMICS"},{"key":"e_1_2_13_42_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2026.1728509","article-title":"The Role of CD36 in Immune Function: Bridging Innate and Adaptive Responses","volume":"17","author":"Zhang X.","year":"2026","journal-title":"Frontiers in Immunology"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70399","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cbdd.70399","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70399","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:09:10Z","timestamp":1790737750000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.70399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":41,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/cbdd.70399"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.70399","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"value":"1747-0277","type":"print"},{"value":"1747-0285","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-06-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70399"}}