{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:04:22Z","timestamp":1789700662693,"version":"4.0.1"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Drug Combinations offer increased therapeutic efficacy and reduced toxicity compared with single agents. Understanding a drug combination's mechanisms of action (MoA) can provide important insights into therapeutic efficacy. The MoA of many FDA\u2010approved drugs, however, often remains unclear. To decipher the underlying molecular mechanisms of drugs used alone and in combination, we investigated the combination of a statin (atorvastatin or simvastatin) plus ezetimibe using drug\u2010treated RNA\u2010seq transcriptome data from the human hepatocyte\u2010like SOAT2\u2010only\u2010HepG2 cells and from liver biopsies of non\u2010obese normolipidemic patients with uncomplicated cholesterol gallstone disease in the Stockholm Study. We proposed a novel Boolean logical modeling framework to simulate the MoA of a drug combination using fourteen two\u2010variable Boolean models. Thereafter, a pattern matching approach was applied to associate drug\u2010induced differentially expressed genes with the idealized differential expression templates derived from Boolean models. We found 1560 and 565 genes differentially expressed in at least one treatment condition in SOAT2\u2010only\u2010HepG2 cells and liver biopsies, respectively. Our analysis revealed both expected and novel combinatorial modes of the statins and ezetimibe. We mapped the downstream genes of each combinatorial mode to the human protein\u2013protein interactome and obtained underlying pathways, which are important for understanding the therapeutic effects of the drug combinations. Functional enrichment and disease\u2010association analyses of the downstream genes also provide critical insights into the additional therapeutic actions of the drugs. Our study demonstrates that drug\u2010induced transcriptomes, integrated with the human interactome, are informative in deciphering the MoA of drug combinations using Boolean logical modeling.<\/jats:p>","DOI":"10.1002\/psp4.70329","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:07:44Z","timestamp":1788264464000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Mechanisms of Statin\u2013Ezetimibe Drug Combinations Using Boolean Logical Modeling and Transcriptomic Data"],"prefix":"10.1002","volume":"15","author":[{"given":"Rui\u2010Sheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine Brigham and Women's Hospital  Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Pedrelli","sequence":"additional","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine and Department of Laboratory Medicine Karolinska Institute  Huddinge Sweden"},{"name":"Medical Unit Endocrinology, Theme Inflammation and Ageing Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osman","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine and Department of Laboratory Medicine Karolinska Institute  Huddinge Sweden"},{"name":"Department of Biochemistry, College of Medicine and Health Sciences Arabian Gulf University  Manama Kingdom of Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garagnani","family":"Paolo","sequence":"additional","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine and Department of Laboratory Medicine Karolinska Institute  Huddinge Sweden"},{"name":"Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna  Bologna 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