{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T06:24:28Z","timestamp":1783059868829,"version":"3.54.6"},"posted":{"date-parts":[[2026,6,29]]},"group-title":"Immunology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"National Heart, Lung, and Blood Institute Division of Intramural Research","award":["HL005199"],"award-info":[{"award-number":["HL005199"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  NAD\u207a supplementation blunts Th1 and Th17 inflammation, in part, through arginine metabolism-dependent regulation of mitochondrial energetics, redox balance and signal transduction. Whether the NAD\n                  <jats:sup>+<\/jats:sup>\n                  -dependent sirtuin deacylases contribute to this regulation is unknown. Here, we show that both SIRT1 and SIRT5 transcript levels are induced in CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells in human participants following oral supplementation of the NAD\n                  <jats:sup>+<\/jats:sup>\n                  precursor nicotinamide riboside (NR). Among the sirtuin family members, SIRT5 rather than SIRT1 emerged as the predominant regulator of arginine and fumarate metabolism. Genetic depletion or pharmacologic inhibition of SIRT5 attenuated NR-mediated increases in arginine and fumarate and abolished the anti-inflammatory -effects of NR on Th1 and Th17 cytokine production. In contrast, the responses to exogenous arginine or citrulline supplementation were preserved, indicating that SIRT5 functions upstream of arginine biosynthesis. Metabolomic profiling further demonstrated that SIRT5 is required for NR-induced remodeling of the arginine biosynthetic pathway. Mechanistically, SIRT5 physically interacted with arginosuccinate lyase (ASL), promoted ASL-dependent arginine accumulation, and regulated ASL post-translational acylation, including glutarylation and malonylation. Loss of SIRT5 disrupted NR-mediated redox homeostasis, antioxidant gene expression, and cytokine suppression. Collectively, these findings identify SIRT5 as a critical mediator of NAD\u207a precursor-induced metabolic remodeling that links ASL-dependent arginine metabolism to redox balance and effector function in human CD4\u207a T cells.\n                <\/jats:p>","DOI":"10.64898\/2026.06.24.734337","type":"posted-content","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:25:12Z","timestamp":1782797112000},"source":"Crossref","is-referenced-by-count":0,"title":["SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function"],"prefix":"10.64898","author":[{"given":"Kim","family":"Han","sequence":"first","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael J.","family":"Klein","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Obesity and Metabolic Diseases, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Chiara","family":"Russo","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison M.","family":"Meadows","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Recupero","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Sharma","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand K.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan T.","family":"Brandes","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, NIAID, NIH, Hamilton, MT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, NIAID, NIH, Hamilton, MT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3411-0000","authenticated-orcid":false,"given":"Michael N.","family":"Sack","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA"},{"name":"Cardiovascular Branch, NHLBI, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070222551809000_2026.06.24.734337v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00313-x"},{"key":"2026070222551809000_2026.06.24.734337v1.2","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1186\/s10020-025-01394-0","article-title":"From Bench to Clinic: The 2024 FASEB Scientific Research Conference on NAD Metabolism and Signaling","volume":"31","year":"2025","journal-title":"Mol Med"},{"key":"2026070222551809000_2026.06.24.734337v1.3","doi-asserted-by":"crossref","unstructured":"Damgaard, M. 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