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The adaptation to low oxygen is regulated by oxygen\u2010sensitive transcription factors, the hypoxia\u2010inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining\n                    <jats:italic>in situ<\/jats:italic>\n                    metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF\u20101\u03b1 as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD\n                    <jats:sup>+<\/jats:sup>\n                    ) levels. The HIF\u20101\u03b1\/NAD\n                    <jats:sup>+<\/jats:sup>\n                    axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steady\u2010state conditions. In contrast, in activated NK cells under hypoxia, HIF\u20101\u03b1 is required for glycolysis, and forced HIF\u20101\u03b1 expression boosts glycolysis and NK cell performance\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Our data highlight two distinct pathways by which HIF\u20101\u03b1 interferes with NK cell metabolism. While HIF\u20101\u03b1\u2010driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF\u20101\u03b1\u2010dependent tryptophan\/NAD\n                    <jats:sup>+<\/jats:sup>\n                    metabolism.\n                  <\/jats:p>","DOI":"10.15252\/embr.202256156","type":"journal-article","created":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T06:26:51Z","timestamp":1680071211000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Resting natural killer cell homeostasis relies on tryptophan\/NAD+ metabolism and HIF\u20101\u03b1"],"prefix":"10.1038","volume":"24","author":[{"given":"Abigaelle","family":"Pelletier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9689-6926","authenticated-orcid":false,"given":"Eric","family":"Nelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Khatchatourova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3678-7143","authenticated-orcid":false,"given":"Abdiel","family":"Alvarado\u2010Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Krzywinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Sobecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunmugam","family":"Nagarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Kerdiles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Fandrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8416-1236","authenticated-orcid":false,"given":"Dagmar","family":"Gotthardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Sexl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"de Bock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-6838","authenticated-orcid":false,"given":"Christian","family":"Stockmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,29]]},"reference":[{"key":"BFEMBR202256156_CR1","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/ni.3838","volume":"18","author":"N Assmann","year":"2017","unstructured":"Assmann N, O'Brien KL, Donnelly RP, Dyck L, Zaiatz\u2010Bittencourt V, Loftus RM, Heinrich P, Oefner PJ, Lynch L, Gardiner CM et\u00a0al (2017) Srebp\u2010controlled glucose metabolism is essential for NK cell functional responses. 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