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Although biologic therapies such as dupilumab have shown clinical efficacy, the molecular mechanisms underlying variable treatment responses remain poorly understood. This study aimed to characterize transcriptomic patterns that distinguish asthmatic patients from healthy controls and to evaluate transcriptomic changes induced by dupilumab. Whole-blood RNA-seq was performed in 66 samples, 18 patients (G0) with severe asthma before and after 6 months of dupilumab treatment compared with 30 non-asthmatic controls. Differentially expressed genes (DEGs) were identified and validated by quantitative PCR (qPCR). Clinical responses were assessed using the FEV1, Exacerbations, Oral corticosteroids, Symptoms (FEOS) score and the Sino-Nasal Outcome Test-22 (SNOT-22). A total of 1124 DEGs were identified, distinguishing asthmatic patients from controls. Notably, ABCC1, CYP4F12, FBN1, IKZF2, and RAB44 were differentially expressed across all patients\u2019 subgroups and are proposed as putative general disease biomarkers. Unsupervised machine learning analysis of pre- vs. post-dupilumab transcriptomic profiles identified two distinct patient subgroups within G0, here termed G1 and G2. When comparing baseline vs. post-treatment samples in the overall cohort (G0), only 12 DEGs were identified. In contrast, stratified analysis revealed 1288 DEGs in G1 and 354 DEGs in G2, suggesting divergent molecular response to treatment. Additionally, baseline expression of DIXDC1 was identified as a predictor of CRSwNP non-super-responders. By applying unsupervised machine learning to transcriptomic profiles, this exploratory study identifies two distinct endotypes with divergent molecular mechanisms of response to dupilumab, supporting a precision medicine approach to biologic therapy in severe asthma.<\/jats:p>","DOI":"10.3390\/ijms27125266","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T02:59:31Z","timestamp":1781146771000},"page":"5266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unsupervised Machine-Learning-Based Endotype Discovery Using Iterative Resampling in Dupilumab-Treated Patients"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1819-3077","authenticated-orcid":false,"given":"Emma","family":"Moreno-Jim\u00e9nez","sequence":"first","affiliation":[{"name":"Departamento de Microbiolog\u00eda y Genetica, Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2779-4512","authenticated-orcid":false,"given":"Natalia","family":"Morgado","sequence":"additional","affiliation":[{"name":"Departamento de Microbiolog\u00eda y Genetica, Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9655-4918","authenticated-orcid":false,"given":"Asunci\u00f3n","family":"Garc\u00eda-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias\u2014RICORS, 28029 Madrid, Spain"},{"name":"Departamento de Biomedicina y Ciencias 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"G\u00f3mez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias\u2014RICORS, 28029 Madrid, Spain"},{"name":"Servicio de Bioqu\u00edmica Cl\u00ednica, Hospital Universitario de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Gil-Melc\u00f3n","sequence":"additional","affiliation":[{"name":"Servicio de Otorhinolaringolog\u00eda y Cirug\u00eda de cabeza y cuello, Hospital Universitario de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milagros","family":"L\u00e1zaro-Sastre","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Servicio de Aergolog\u00eda Department, Hospital Universitario de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2974-0873","authenticated-orcid":false,"given":"Catalina","family":"Sanz","sequence":"additional","affiliation":[{"name":"Departamento de Microbiolog\u00eda y Genetica, Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias\u2014RICORS, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Isidoro-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias\u2014RICORS, 28029 Madrid, Spain"},{"name":"Servicio de Bioqu\u00edmica Cl\u00ednica, Hospital Universitario de Salamanca, 37007 Salamanca, Spain"},{"name":"Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8485-5513","authenticated-orcid":false,"given":"Ignacio","family":"D\u00e1vila","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias\u2014RICORS, 28029 Madrid, Spain"},{"name":"Departamento de Biomedicina y Ciencias del Diagnostico, Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Servicio de Aergolog\u00eda Department, Hospital Universitario de Salamanca, 37007 Salamanca, 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