Abstract: International Journal of Molecular Sciences Article Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells Amene Majidipur 1 , Margot Morin-Dewaele 2, Jeanne Gaspar Lopes 1, Francois Berry 2, Julien Fouchet 1, Sophie Bartier 3,4,5, Anais Dufros Duval 1, Pascale Soyeux 1, Eric Huet 1 , Bruno Louis 5, André Coste 3,4,5, Émilie Béquignon 3,4,5 , Carolina Saldana 1,6, Philippe Le Corvoisier 7, Damien Destouches 1 , Jean-Michel Pawlotsky 2,8, Alexandre de la Taille 1,6,9, Francis Vacherot 1, Patrice Bruscella 2,† and Virginie Firlej 1,*,† 1 2 3 4 5 6 7 8 9 * † Citation: Majidipur, A.; MorinDewaele, M.; Gaspar Lopes, J.; Berry, F.; Fouchet, J.; Bartier, S.; Dufros Duval, A.; Soyeux, P.; Huet, E.; Louis, B.; et al. Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells. Int. J. Mol. Sci. 2023, 24, 3288. https://doi.org/10.3390/ ijms24043288 Academic Editor: Francesco B. Blasi Received: 5 December 2022 TRePCa, Université Paris Est Créteil, F-94010 Créteil, France Team “Viruses, Hepatology, Cancer”, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, INSERM U955, F-94010 Créteil, France Department of ENT and Head and Neck Surgery, Centre Hospitalier Intercommunal de Créteil, F-94010 Créteil, France AP-HP, Department of ENT and Head and Neck Surgery, Centre Hospitalier Universitaire Henri Mondor, F-94010 Créteil, France Team “Biomechanics and Respiratory System“, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, INSERM U955, CNRS EMR 7000, F-94010 Créteil, France AP-HP, Department of Oncology, Centre Hospitalier Universitaire Henri Mondor, F-94010 Créteil, France INSERM, AP-HP, Clinical Investigation Center 1430, Henri Mondor University Hospital, F-94000 Créteil, France AP-HP, Department of Virology, Centre Hospitalier Universitaire Henri Mondor, F-94010 Créteil, France AP-HP, Department of Urology, Centre Hospitalier Universitaire Henri Mondor, F-94010 Créteil, France Correspondence: virginie.firlej@u-pec.fr; Tel.: +33-1-49-81-36-14 These authors contributed equally to this work. Abstract: In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19. Keywords: SARS-CoV-2; androgen; ARPI; TMPRSS2 Revised: 29 January 2023 Accepted: 2 February..