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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:p>\n                    Global warming\u2013induced aquatic deoxygenation poses a severe physiological challenge to teleosts, often influencing their immune defense mechanisms. While aquatic organisms are under evolutionary pressure to balance metabolic adaptation with pathogen resistance, the molecular strategies they employ to overcome high pathogen loads under hypoxic stress remain poorly understood. Here, an oxygen\u2013immunity regulatory axis was identified in teleosts, in which the oxygen sensor FIH (factor inhibiting HIF) activated the NF-\u03baB pathway by competitively displacing p65 from I\u03baB\u03b1. Experiments with FIH mutants showed that NF-\u03baB activation did not require FIH hydroxylase activity. In vitro, FIH bound I\u03baB\u03b1, promoted p65 nuclear translocation, and increased inflammatory gene expression. FIH knockdown blunted these responses. In vivo, CRISPR\/Cas9-generated\n                    <jats:italic toggle=\"yes\">drfih<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    zebrafish showed reduced NF-\u03baB-driven inflammation, altered responses to LPS challenge, and a dose-dependent trade-off in\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">Vibrio<\/jats:italic>\n                      anguillarum\n                    <\/jats:italic>\n                    infection, with reduced resistance at a low dose but mitigated immunopathology at a high dose. AlphaFold3 modeling and mutational analyses pinpointed a competitive interface. In human cells, FIH\u2013I\u03baB\u03b1 binding occurred without NF-\u03baB activation. Notably, replacing a C-terminal segment of human I\u03baB\u03b1 with the teleost counterpart restored FIH-dependent competition and NF-\u03baB activation, indicating lineage-specific structural divergence. Extensive cross-species predictions revealed that several aquatic vertebrates, an amphibian, and a shrimp species possessed a competitive interface, whereas the terrestrial species examined did not. These findings revealed a hydroxylase-independent mechanism, likely associated with aquatic lineages, that linked oxygen sensing to innate immunity and had implications for vertebrate evolution, climate-driven hypoxia, and aquaculture health.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2529211123","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:08:59Z","timestamp":1781712539000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["A teleost-specific oxygen\u2013immunity axis where FIH activates NF-\u03baB via competitive I\u03baB\u03b1 binding"],"prefix":"10.1073","volume":"123","author":[{"given":"Zhipeng","family":"Zhan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences, China-Association of Southeast Asian Nations (ASEAN) Belt and Road Joint Laboratory on Mariculture 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