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They can cause a wide spectrum of respiratory illnesses, ranging from mild upper respiratory tract infections to severe pneumonia, and acute respiratory distress syndrome. PTEN, a well-known tumor suppressor, not only plays a crucial role in tumorigenesis but also enhances antiviral immunity by regulating IRF3 phosphorylation and promoting type I interferon production. In this study, we observed that PTEN significantly inhibited the replication of various HCoVs, including SARS-CoV-2, HCoV-229E, and HCoV-OC43. However, SARS-CoV-2 infection antagonizes the antiviral function of PTEN. Mechanistically, PTEN undergoes ubiquitination at lysine 6, followed by proteasomal degradation after SARS-CoV-2 infection. Through screening, it was found that STUB1 is the key E3 ligase responsible for PTEN degradation under SARS-CoV-2 infection. Furthermore, screening of SARS-CoV-2-encoded proteins revealed that ORF3a promotes STUB1-mediated PTEN ubiquitination and degradation at K6. Previous studies have shown that Oroxin B can exert the effect of a PTEN agonist by upregulating the expression of PTEN. In this study, we demonstrated that Oroxin B significantly enhances antiviral responses in mice. In conclusion, this study reveals the molecular mechanism by which SARS-CoV-2 evades PTEN-mediated antiviral effects, providing new insights for the development of PTEN-targeted antiviral strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Human coronaviruses continue to threaten global health, yet how these viruses evade our natural antiviral defenses remains poorly understood. This study reveals that PTEN, a well-known tumor suppressor, also acts as a powerful antiviral molecule capable of limiting multiple human coronaviruses, including SARS-CoV-2. We further show that SARS-CoV-2 dismantles this protection by triggering PTEN degradation through the host enzyme STUB1 and the viral protein ORF3a. This discovery uncovers a previously unknown strategy used by coronaviruses to weaken innate immunity. Importantly, we identify Oroxin B as a promising compound that enhances antiviral responses\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . Together, our findings provide new insight into how coronaviruses disarm host defenses and highlight PTEN as a potential target for broad-spectrum antiviral therapies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00186-26","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T13:20:04Z","timestamp":1780406404000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["SARS-CoV-2 ORF3a suppresses host antiviral interferon responses by promoting STUB1-mediated PTEN proteasomal degradation"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2113-7308","authenticated-orcid":false,"given":"Lujie","family":"Fan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049tv2d57","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Hepatology, National Clinical Research Center for Infectious 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