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Identifying an altered profile of circulating miRNAs in mild COVID-19 may enhance our knowledge of the pathogenesis of SARS-CoV-2 and the range of clinical phenotypes. In the present study, a miRNA screening was performed by Next Generation Sequencing (NGS), and the expression levels of 13 resulting miRNAs were validated through RT-qPCR in the serum of 40 mild cases compared to 29 non-infected individuals. An in-silico analysis was performed to detect target genes and their related pathways. From the validated miRNAs, miR-1246 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), miR-423-5p (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), miR-21-5p (<jats:italic>p<\/jats:italic>\u2009=\u20090.005), miR-146a-5p (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), miR-4508 (<jats:italic>p<\/jats:italic>\u2009=\u20090.001), miR-629-5p (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), and miR-210-3p (<jats:italic>p<\/jats:italic>\u2009=\u20090.002) were found downregulated in infected individuals. Only miR-27a-5p was overexpressed in subjects with COVID-19 (<jats:italic>p<\/jats:italic>\u2009=\u20090.013) and associated with SARS-CoV-2 infection (<jats:italic>p<\/jats:italic>\u2009=\u20090.010). The KEGG pathways and GO analysis revealed that the differentially expressed miRNAs were related to viral processes or immunological pathways: miR-27a-5p acts on the TGF-beta pathway; miR-21-5p targets <jats:italic>SMAD7<\/jats:italic>, which is associated with the inflammatory response in the lung; miR-1246 acts on p53 pathway; and miR-4508 acts on <jats:italic>ICAM2<\/jats:italic>. In conclusion, the most relevant miRNAs, miR-27a-5p and miR-21-5p, were differently expressed in mild forms of COVID-19. The higher expression of miR-27a-5p observed in mild COVID-19 cases may suggest a protective effect against severe forms of the disease. Reduced expression of miR-21-5p may prevent pulmonary inflammation and the progression of fibrosis. The downregulation of miR-1246 and miR-4508 in mild COVID-19 cases may conduct the correct control of the infection. Moreover, miR-423-5p might be a suitable biomarker in the early stages of SARS-CoV-2 infection.<\/jats:p>","DOI":"10.1186\/s10020-025-01154-0","type":"journal-article","created":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T15:27:31Z","timestamp":1742052451000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["miR-27a-5p, miR-21-5p, miR-1246 and miR-4508: a candidate microRNA signature in the protection and regulation of viral infection in mild COVID-19"],"prefix":"10.1186","volume":"31","author":[{"given":"Malena","family":"Gajate-Arenas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candela","family":"Sirvent-Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Garc\u00eda-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lica","family":"Dom\u00ednguez-de-Barros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 E.","family":"Pi\u00f1ero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Lorenzo-Morales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"C\u00f3rdoba-Lan\u00fas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"1154_CR1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nri1391","volume":"4","author":"S Akira","year":"2004","unstructured":"Akira S, Takeda K. 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