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Recent systems biology analyses identified four potential molecular triggers\u2014AKT1, MAPK13, STAT1, and TLR4\u2014as candidate regulators of asthma-associated signaling pathways. This study aimed to validate the expression of these four proteins and their downstream signaling elements in peripheral blood mononuclear cells (PBMCs) from patients with allergic asthma (AA), nonallergic asthma (NA), and healthy controls (HC), to explore their potential as biomarkers or therapeutic targets. For that, PBMC samples were collected from 45 AA patients, 17 NA patients, and 15 HC subjects. Gene and protein expression of AKT1, MAPK13, STAT1, and TLR4 were quantified using RT-qPCR and Western blotting. Expression patterns were compared across groups and stratified by asthma severity. Correlations with clinical parameters (FEV1, FVC, FeNO, IgE, eosinophil counts) and treatment regimens were also assessed. All four target genes showed significantly reduced expression in asthma patients compared to controls (p &lt; 0.001), with the most marked downregulation in NA patients. At the protein level, MAPK13 and TLR4 showed significant differential expression. Stratification by severity revealed a stepwise reduction in gene expression in AA patients, correlating with disease severity, whereas NA patients showed uniformly low expression regardless of severity. Multiple pathway-related genes, including RELA, SMAD3, NFATC1, and ALOX5, were also downregulated, particularly in NA patients. Notably, differential correlations were observed between gene expression and lung function parameters in AA vs. NA groups. In conclusion, this study supports the potential involvement of AKT1, MAPK13, STAT1, and TLR4 in asthma pathogenesis and highlights differences between allergic and nonallergic asthma at the molecular level. These proteins and their associated pathways may serve as future targets for biomarker development or endotype-specific therapies. Further studies in larger and more diverse cohorts, including functional validation, are warranted.<\/jats:p>","DOI":"10.3390\/ijms26136240","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6240","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular Study from the Signaling Pathways of Four Potential asthma triggers: AKT1, MAPK13, STAT1, and TLR4"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8094-5295","authenticated-orcid":false,"given":"Luc\u00eda","family":"Cremades-Jimeno","sequence":"first","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"L\u00f3pez-Ramos","sequence":"additional","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-4280","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Fern\u00e1ndez-Santamar\u00eda","sequence":"additional","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8989-2468","authenticated-orcid":false,"given":"Mar\u00eda \u00c1ngeles","family":"De Pedro","sequence":"additional","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0558-6541","authenticated-orcid":false,"given":"Ignacio","family":"Mahillo","sequence":"additional","affiliation":[{"name":"Biostatistics and Epidemiology Unit, University Hospital Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rosales-Ariza","sequence":"additional","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Olaguibel","sequence":"additional","affiliation":[{"name":"Allergology Service, University Hospital of Navarra, 31008 Pamplona, Spain"},{"name":"Ciber de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6228-1969","authenticated-orcid":false,"given":"Victoria del","family":"Pozo","sequence":"additional","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, Spain"},{"name":"Ciber de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9207-6445","authenticated-orcid":false,"given":"Mar\u00eda Luisa","family":"Caballero","sequence":"additional","affiliation":[{"name":"Ciber de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain"},{"name":"Department of Allergy, La Paz University Hospital, IdiPAZ, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0280-0143","authenticated-orcid":false,"given":"Juan Alberto","family":"Luna-Porta","sequence":"additional","affiliation":[{"name":"Ciber de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain"},{"name":"Department of Allergy, La Paz University Hospital, IdiPAZ, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8086-0921","authenticated-orcid":false,"given":"Santiago","family":"Quirce","sequence":"additional","affiliation":[{"name":"Ciber de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain"},{"name":"Department of Allergy, La Paz University Hospital, IdiPAZ, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Barroso","sequence":"additional","affiliation":[{"name":"Allergy Department, University Hospital Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Betancor","sequence":"additional","affiliation":[{"name":"Allergy Department, University Hospital Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Valverde-Monge","sequence":"additional","affiliation":[{"name":"Allergy Department, University Hospital Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Sastre","sequence":"additional","affiliation":[{"name":"Ciber de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain"},{"name":"Allergy Department, University Hospital Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6398-417X","authenticated-orcid":false,"given":"Selene","family":"Baos","sequence":"additional","affiliation":[{"name":"Immunology Department, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz-UAM, 28040 Madrid, 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