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Although resistance pathways are well characterized, the molecular determinants of host tolerance remain poorly understood. Here, we demonstrate that vanin-1, an ectoenzyme known for its role in vitamin B5 metabolism, unexpectedly regulates host tolerance during influenza infection through modulation of cellular redox status. Mice lacking vanin-1 showed enhanced survival following lethal influenza infection without alterations in viral burden, immune responses, or tissue pathology. While vanin-1 deficiency impairs vitamin B5 metabolism, neither vitamin B5 supplementation nor deficiency affected survival during infection, indicating a vitamin B5\u2013independent mechanism. RNA sequencing analysis revealed enhanced expression of antioxidant pathway genes in vanin-1\u2013deficient mice, with Nrf2 serving as a key upstream regulator. Mechanistically, vanin-1\u2013deficient mice maintained higher glutathione levels during infection and showed reduced lipid peroxidation, suggesting protection against oxidative stress-induced cell death. Importantly, pharmacological inhibition of glutathione synthesis abolished the survival advantage in vanin-1\u2013deficient mice, while glutathione supplementation protected wild-type mice from lethal infection. Our findings reveal an unexpected role for vanin-1 in regulating host tolerance through antioxidant pathways and identify a potential therapeutic target for enhancing survival during severe viral infections.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgag222","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T08:34:58Z","timestamp":1782117298000},"source":"Crossref","is-referenced-by-count":0,"title":["Vanin-1 deficiency enhances host tolerance to influenza infection by modulating cellular redox status"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0132-9273","authenticated-orcid":false,"given":"Jin Soo","family":"Joo","sequence":"first","affiliation":[{"name":"Department of Systems Biology, Yonsei University , Seoul 03722 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Pasman","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3657-7625","authenticated-orcid":false,"given":"Shuang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2055-5885","authenticated-orcid":false,"given":"Robert","family":"Homer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Naquet","sequence":"additional","affiliation":[{"name":"Centre D'Immunologie de Marseille-Luminy, INSERM, CNRS, Aix-Marseille Universit\u00e9 , 13288 Marseille , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7021-2012","authenticated-orcid":false,"given":"Ruslan","family":"Medzhitov","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Howard Hughes Medical Institute , Chevy Chase, MD 20815 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4963-7147","authenticated-orcid":false,"given":"Jun Young","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Yonsei University , Seoul 03722 ,","place":["South Korea"]},{"name":"Department of Immunobiology, Yale University School of Medicine , New Haven, CT 06510 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