{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:42:55Z","timestamp":1791996175548,"version":"4.4.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Angiotensin\u2010converting enzyme 2 (ACE2), the receptor for SARS\u2010CoV\u20102, is critical for viral entry and pulmonary homeostasis, yet its regulation during infection remains unclear. Using SARS\u2010CoV\u20102 single\u2010round infectious particles (SRIPs), we found that ACE2 protein and mRNA were markedly reduced in human alveolar (A549) and bronchial (Calu\u20103) cells. This effect was reproduced by expression of the viral main protease (Mpro). Notably, ACE2 suppression was independent of Mpro enzymatic activity, as the catalytically inactive mutant (Mpro_C145A) downregulated ACE2 comparably to wild\u2010type Mpro, and inhibition with nirmatrelvir or MG132 failed to restore expression. Mechanistically, Mpro enhanced STAT1 phosphorylation while suppressing STAT3 Tyr705 phosphorylation, impairing STAT3 nuclear localization and transcriptional activity. Overexpression of STAT3, but not STAT1, restored ACE2 expression in both Mpro\u2010expressing and SARS\u2010CoV\u20102\u2013infected cells. Moreover, Mpro activated ERK1\/2 through TRAF6\u2013TAK1 signaling, which facilitated STAT3 interaction with the tyrosine phosphatase MEG2, leading to dephosphorylation of STAT3 at Tyr705. ERK1\/2 inhibition restored STAT3 activity and ACE2 expression, while JNK inhibition had no effect. In infected cells, ERK1\/2 inhibition increased ACE2 but also enhanced viral replication. These findings identify a non\u2010enzymatic role of Mpro in suppressing ACE2 through the ERK1\/2\u2013MEG2\u2013STAT3 axis, highlighting a mechanism that regulates host receptor availability and influences SARS\u2010CoV\u20102 pathogenesis.<\/jats:p>","DOI":"10.1002\/jmv.70855","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:04:35Z","timestamp":1772989475000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SARS\u2010CoV\u20102 Main Protease Activates ERK1\/2 Signaling to Facilitate MEG2\u2013STAT3\u2010Mediated Suppression of ACE2"],"prefix":"10.1002","volume":"98","author":[{"given":"Uyen Nguyen","family":"Phuong Le","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology China Medical University Taichung Taiwan"},{"name":"Graduate Institute of Biological Science and Technology China Medical University Taichung 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