{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:40:07Z","timestamp":1792510807485,"version":"4.5.0"},"reference-count":27,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      H9N2 avian influenza virus (AIV) poses significant threats to poultry and public health, with the potential to contribute to the emergence of more virulent influenza strains. Hypoxia-inducible factor 1-alpha (HIF-1\u03b1) plays a crucial role in viral pathogenesis, immune regulation, and inflammation, making it a promising target for therapeutic intervention. Here, we explored the involvement of HIF-1\u03b1 in H9N2 AIV pathogenesis and associated inflammatory responses. Our data revealed that HIF-1\u03b1 exacerbates inflammation induced by H9N2 AIV infection through its regulation of mitochondrial fitness. Additionally, we investigated Sotetsuflavone (Seo), a naturally derived flavonoid, for its potential to modulate inflammatory responses following H9N2 infection. Molecular docking coupled with surface plasmon resonance assays indicated that Seo exhibits robust binding affinity to HIF-1\u03b1, implying a direct inhibitory mechanism. Subsequent\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      studies demonstrated that Seo greatly reduced the production of inflammatory cytokines, including IL-1\u03b2, IL-6, and TNF-\u03b1, through suppressing the HIF-1\u03b1 signaling pathway in HD11 cells infected with H9N2 AIV. Correspondingly,\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      experiments established that Seo administration significantly ameliorated pulmonary inflammation in H9N2-infected mice, while also enhancing alveolar epithelial repair, as evidenced by increased expression of type II alveolar epithelial cell markers Abca3 and Sftpb. Collectively, these findings identify Seo as a potent inhibitor of HIF-1\u03b1, highlighting its therapeutic potential in mitigating inflammation and lung damage associated with influenza virus infection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        H9N2 avian influenza virus triggers inflammatory lung injury via hypoxia-inducible factor-1 alpha (HIF-1\u03b1)-mediated dysregulation of mitochondrial function. The natural flavonoid Sotetsuflavone (Seo) directly binds and inhibits HIF-1\u03b1, as confirmed by molecular docking and surface plasmon resonance assays. In H9N2-infected HD11 cells, Seo suppresses HIF-1\u03b1 signaling, reducing IL-1\u03b2, IL-6, and TNF-\u03b1 production.\n                        <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                        , Seo treatment attenuates pulmonary inflammation and enhances alveolar epithelial repair in mice, upregulating type II pneumocyte markers (Abca3 and Sftpb). These findings identify Seo as a promising HIF-1\u03b1-targeted therapeutic for influenza-associated immunopathology.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02680-25","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T20:54:17Z","timestamp":1787691257000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia-inducible factor 1-alpha inhibition mitigates inflammatory responses induced by H9N2 avian influenza virus"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4965-3421","authenticated-orcid":true,"given":"Suying","family":"Zhu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041zje040","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Agriculture and Bioengineering, Heze University","place":["Heze, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041zje040","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Agriculture and Bioengineering, Heze University","place":["Heze, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqi","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041zje040","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Agriculture and Bioengineering, Heze University","place":["Heze, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Tian","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041zje040","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Agriculture and Bioengineering, Heze University","place":["Heze, 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