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However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS\u2010CoV\u20102 infection via upregulating angiotensin\u2010converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene <jats:italic>trans<\/jats:italic>\u2010activates the promoters of <jats:italic>ACE2<\/jats:italic> and <jats:italic>TMPRSS2<\/jats:italic> by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in <jats:italic>ACE2<\/jats:italic> and <jats:italic>TMPRSS2<\/jats:italic>. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS\u2010CoV\u20102 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or\u00a0interferon\u2010\u03bb2\/\u03bb3 stimulation\u00a0downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS\u2010CoV\u20102 infection by boosting NR4A2\u2010induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS\u2010CoV\u20102 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.<\/jats:p>","DOI":"10.1002\/advs.202300834","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T11:33:56Z","timestamp":1688988836000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Smoke and Spike: Benzo[a]pyrene Enhances SARS\u2010CoV\u20102 Infection by Boosting NR4A2\u2010Induced ACE2 and TMPRSS2 Expression"],"prefix":"10.1002","volume":"10","author":[{"given":"Wenbin","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Biosafety Defense Ministry of Education  Shanghai 200433 China"},{"name":"Shanghai Key Laboratory of Medical Biodefense  Shanghai 200433 China"},{"name":"Department of Epidemiology Second Military Medical 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