DOI record: { "DOI": "10.3389/fcimb.2026.1976945", "ISSN": [ "2235-2988" ], "URL": "http://dx.doi.org/10.3389/fcimb.2026.1976945", "abstract": "<jats:sec>\n <jats:title>Introduction</jats:title>\n <jats:p>Sex-related differences in coronavirus disease 2019 (COVID-19) severity suggest an important role for sex steroids in regulating immune and endothelial responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>\n Receptor expression, inflammatory signaling, and monocyte transendothelial migration were assessed by RT-PCR, immunoblotting, and Boyden chamber assay, respectively. HULEC-5a and primary human immune cells were exposed to\n <jats:italic>in vitro</jats:italic>\n -amplified SARS-CoV-2. Samples were collected between June 2020 and April 2022, with sample sizes based on primary sample availability and independent experiments.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>SARS-CoV-2 differentially regulates estrogen receptor gene expression, decreasing it in endothelial cells (p&amp;lt;0.05) while increasing it in immune cells (p&amp;lt;0.01). SARS-CoV-2 generally activated inflammatory signaling pathways, including NFκB, STAT3, and p38 MAPK, in THP-1 monocytic cells (up to 1.9-fold). The NFκB response was augmented by the androgen receptor agonist dihydrotestosterone (DHT, 44.6%) and attenuated by the androgen receptor antagonist flutamide (44.1%). In endothelial cells, DHT twice reduced SARS-CoV-2 activation of the p38 MAPK signaling pathway. β-estradiol inhibited (2.2-fold), whereas DHT stimulated (4.9-fold) NFκB signaling pathway in neutrophils isolated from patients with COVID-19. SARS-CoV-2 activation of inflammatory signaling pathways deteriorates over time in monocytes from patients with COVID-19 (p&amp;lt;0.05). Furthermore, DHT significantly increased trans-endothelial migration of monocytes (p&amp;lt;0.001) and detachment of SARS-CoV-2 exposed endothelial cells (p&amp;lt;0.01), suggesting a potential role for androgen-responsive pathways in endothelial dysfunction and immune cell trafficking.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Discussion</jats:title>\n <jats:p>These findings elucidate the molecular mechanisms driving male-biased COVID-19 severity and underscore the potential of targeting androgen-responsive pathways as a therapeutic strategy to mitigate severe viral inflammation and endothelial dysfunction.</jats:p>\n </jats:sec>", "alternative-id": [ "10.3389/fcimb.2026.1976945" ], "article-number": "1976945", "author": [ { "affiliation": [ { "name": "Department of Molecular Oncology, Clinic of Hematology, University Clinical Center of Serbia", "place": [ "Belgrade, Serbia" ] } ], "family": "Bižić-Radulović", "given": "Sandra", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "first" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade", "place": [ "Belgrade, Serbia" ] } ], "family": "Subotički", "given": "Tijana", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute of Virology, Vaccines and Sera “Torlak”", "place": [ "Belgrade, Serbia" ] } ], "family": "Kovačević", "given": "Ana", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade", "place": [ "Belgrade, Serbia" ] } ], "family": "Živković", "given": "Emilija", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute of Virology, Vaccines and Sera “Torlak”", "place": [ "Belgrade, Serbia" ] } ], "family": "Popović", "given": "Olga", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade", "place": [ "Belgrade, Serbia" ] } ], "family": "Mitrović-Ajtić", "given": "Olivera", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade", "place": [ "Belgrade, Serbia" ] } ], "family": "Diklić", "given": "Miloš", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Microbiology, University Clinical Centre of Serbia", "place": [ "Belgrade, Serbia" ] } ], "family": "Jovanović", "given": "Snežana", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade", "place": [ "Belgrade, Serbia" ] } ], "family": "Čokić", "given": "Vladan P.", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Department of Molecular Oncology, Institute of Virology, Vaccines and Sera “Torlak”", "place": [ "Belgrade, Serbia" ] } ], "family": "Beleslin-Čokić", "given": "Bojana", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" } ], "container-title": "Frontiers in Cellular and Infection Microbiology", "container-title-short": "Front. 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