{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:28:38Z","timestamp":1787243318968,"version":"build-2736575974"},"posted":{"date-parts":[[2026,1,21]]},"group-title":"Immunology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["ZIA-HL005102"],"award-info":[{"award-number":["ZIA-HL005102"]}],"id":[{"id":"https:\/\/ror.org\/023ny1p48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  In contrast to Krebs cycle intermediates, the role of mitochondrial fatty acid oxidation (FAO) in immunometabolism remains incompletely characterized. Studying primary bone marrow-derived macrophages (BMDMs), we show that IFN-\u03b2 and STING activation augments FAO and associated enzymes carnitine palmitoyltransferase 1a (CPT1a) and acetyl-CoA acetyltransferase 1 (ACAT1). Depleting BMDM\n                  <jats:italic>Cpt1a<\/jats:italic>\n                  reduces FAO and dampens type 1 interferon (IFN) signaling due to decreased histone H3-K9\/K14 acetylation, supporting the prior finding of an epigenetic role of FAO in sustaining type 1 IFN. Interestingly, FAO induction by IFN was dynamic as a heightened IFN response suppressed FAO, suggesting a concurrent negative-feedback mechanism. This FAO blunting correlated with increased expression of interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier known to modulate metabolic proteins through ISGylation. This immune-metabolic signature was similarly operational in mice infected with lymphocytic choriomenigitis virus (LCMV) with temporal discordance between ISG15 levels and FAO. The role of ISG15 in this negative feedback was shown with increased FAO and type 1 IFN response in\n                  <jats:italic>Isg15<\/jats:italic>\n                  knockout BMDMs. Parallely, endogenous co-immunoprecipitation showed interactions between ISG15 and CPT1a\/ACAT1. This ISG15-FAO regulatory interaction was also evident in systemic lupus erythematosus (SLE)-associated interferonopathy and in primary monocytes from SLE individuals that exhibited increased ISG15 levels and reduced FAO rates. Collectively, these findings support a model in which type 1 IFN initially enhances FAO to amplify interferon production, but excessive IFN-signaling induces ISG15-mediated inhibition of FAO, a putative feedback loop that restrains inflammation and preserves immune homeostasis. Together these data identify a novel biphasic FAO-dependent immunometabolic regulatory program.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Summary<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"700051v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Type 1 IFN rewires myeloid cell metabolism towards FAO.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>FAO epigenetically fuels Type 1 1IFN response.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Effect of IFN on FAO is dynamic: inducing FAO at low concentrations while suppressing it during a heightened IFN response.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Enhanced Type 1 IFN response produces ISG15 which ISGylates key enzymes of FAO altering their stability<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>ISG15 negatively regulates FAO to control Type 1 IFN homeostasis in a negative feedback loop.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.19.700051","type":"posted-content","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T07:10:24Z","timestamp":1769065824000},"source":"Crossref","is-referenced-by-count":1,"title":["ISG15 orchestrates dynamic crosstalk between mitochondrial fat oxidation and type 1 interferon in myeloid cells"],"prefix":"10.64898","author":[{"given":"Anand Kumar","family":"Gupta","sequence":"first","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pijush","family":"Das","sequence":"additional","affiliation":[{"name":"Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Sharma","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonali","family":"Das","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Han","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael J.","family":"Klein","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca D.","family":"Huffstutler","sequence":"additional","affiliation":[{"name":"Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Combs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren J.","family":"Leonard","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kemper","sequence":"additional","affiliation":[{"name":"Laboratory for Complement and Inflammation Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin E.","family":"West","sequence":"additional","affiliation":[{"name":"Laboratory for Complement and Inflammation Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 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, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"},{"name":"Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020608174905000_2026.01.19.700051v1.1","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1172\/JCI120845","article-title":"Mitochondrial fidelity and metabolic agility control immune cell fate and function","volume":"128","year":"2018","journal-title":"J Clin Invest"},{"key":"2026020608174905000_2026.01.19.700051v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.70"},{"key":"2026020608174905000_2026.01.19.700051v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature11986"},{"key":"2026020608174905000_2026.01.19.700051v1.4","doi-asserted-by":"crossref","first-page":"106578","DOI":"10.1016\/j.isci.2023.106578","article-title":"N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4(+)T cell responsiveness","volume":"26","year":"2023","journal-title":"iScience"},{"key":"2026020608174905000_2026.01.19.700051v1.5","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1093\/jleuko\/qiae006","article-title":"Propionate functions as a feeding state-dependent regulatory metabolite to counter proinflammatory signaling linked to nutrient load and obesity","volume":"115","year":"2024","journal-title":"J Leukoc Biol"},{"key":"2026020608174905000_2026.01.19.700051v1.6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2020.09.014","article-title":"Modification of Proteins by Metabolites in Immunity","volume":"54","year":"2021","journal-title":"Immunity"},{"key":"2026020608174905000_2026.01.19.700051v1.7","doi-asserted-by":"crossref","first-page":"eadq9301","DOI":"10.1126\/sciadv.adq9301","article-title":"Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation","volume":"11","year":"2025","journal-title":"Sci Adv"},{"key":"2026020608174905000_2026.01.19.700051v1.8","doi-asserted-by":"crossref","unstructured":"Chowdhury, N. U. , J. Y. Cephus , E. Henriquez Pilier , M. M. Wolf , M. Z. Madden , S. N. Kuehnle , K. E. McKernan , E. Q. Jennings , E. N. Arner , D. R. Heintzman , C. Chi , A. Sugiura , M. T. Stier , K. Voss , X. Ye , K. L. Scales , E. S. Krystofiak , V. D. Gandhi , R. D. Guzy , K. N. Cahill , A. I. Sperling , R. S. Peebles, Jr. , J. C. Rathmell , and D. C. Newcomb . 2024. Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation. J Clin Invest.","DOI":"10.1172\/JCI177242"},{"key":"2026020608174905000_2026.01.19.700051v1.9","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12858"},{"key":"2026020608174905000_2026.01.19.700051v1.10","doi-asserted-by":"crossref","unstructured":"Peace, C. G. , and L. A. O\u2019Neill . 2022. The role of itaconate in host defense and inflammation. J Clin Invest 132.","DOI":"10.1172\/JCI148548"},{"key":"2026020608174905000_2026.01.19.700051v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2017.12.011"},{"key":"2026020608174905000_2026.01.19.700051v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36941-9"},{"key":"2026020608174905000_2026.01.19.700051v1.13","doi-asserted-by":"crossref","first-page":"12676","DOI":"10.1038\/srep12676","article-title":"Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"2026020608174905000_2026.01.19.700051v1.14","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/s42255-025-01273-2","article-title":"NK cell-derived IFNgamma mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection","volume":"7","year":"2025","journal-title":"Nat Metab"},{"key":"2026020608174905000_2026.01.19.700051v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.06.006"},{"key":"2026020608174905000_2026.01.19.700051v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.12.007"},{"key":"2026020608174905000_2026.01.19.700051v1.17","doi-asserted-by":"crossref","first-page":"e0389322","DOI":"10.1128\/spectrum.03893-22","article-title":"ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection","volume":"10","year":"2022","journal-title":"Microbiol Spectr"},{"key":"2026020608174905000_2026.01.19.700051v1.18","doi-asserted-by":"crossref","first-page":"1353336","DOI":"10.3389\/fimmu.2024.1353336","article-title":"5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation","volume":"15","year":"2024","journal-title":"Front Immunol"},{"key":"2026020608174905000_2026.01.19.700051v1.19","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/j.immuni.2024.06.001","article-title":"A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance","volume":"57","year":"2024","journal-title":"Immunity"},{"key":"2026020608174905000_2026.01.19.700051v1.20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131556"},{"key":"2026020608174905000_2026.01.19.700051v1.21","doi-asserted-by":"publisher","DOI":"10.1039\/c9cc09993j"},{"key":"2026020608174905000_2026.01.19.700051v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay1109"},{"key":"2026020608174905000_2026.01.19.700051v1.23","doi-asserted-by":"crossref","unstructured":"Zhu, J. , G. Liu , J. Xu , K. Li , C. M. Goins , H. Yu , Z. Sayyad , Y. Zhou , E. White , O. Fiehn , S. R. Stauffer , F. Cheng , and M. U. Gack . 2025. Dysregulation of innate immunity and cellular metabolism through virus-induced deISGylation. bioRxiv.","DOI":"10.1101\/2025.09.08.674928"},{"key":"2026020608174905000_2026.01.19.700051v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13393-x"},{"key":"2026020608174905000_2026.01.19.700051v1.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.23.11012"},{"key":"2026020608174905000_2026.01.19.700051v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107633"},{"key":"2026020608174905000_2026.01.19.700051v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35209-1"},{"key":"2026020608174905000_2026.01.19.700051v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nature13801"},{"key":"2026020608174905000_2026.01.19.700051v1.29","doi-asserted-by":"crossref","first-page":"116254","DOI":"10.1016\/j.celrep.2025.116254","article-title":"FABP5 in skin macrophages mediates saturated fat-induced IL-1beta signaling in psoriatic inflammation","volume":"44","year":"2025","journal-title":"Cell Rep"},{"key":"2026020608174905000_2026.01.19.700051v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.09.041"},{"key":"2026020608174905000_2026.01.19.700051v1.31","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01650-07"},{"key":"2026020608174905000_2026.01.19.700051v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202451651"},{"key":"2026020608174905000_2026.01.19.700051v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2009.23"},{"key":"2026020608174905000_2026.01.19.700051v1.34","doi-asserted-by":"crossref","unstructured":"Wu, J. , K. Singh , A. Lin , A. M. Meadows , K. Wu , V. Shing , M. Bley , S. Hassanzadeh , R. D. Huffstutler , M. S. Schmidt , L. P. Blanco , R. Tian , C. Brenner , M. Pirooznia , M. J. Kaplan , and M. N. Sack . 2022. Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes. J Clin Invest 132.","DOI":"10.1172\/JCI139828"},{"key":"2026020608174905000_2026.01.19.700051v1.35","doi-asserted-by":"crossref","unstructured":"Yan, S. , M. Kumari , H. Xiao , C. Jacobs , S. Kochumon , M. Jedrychowski , E. Chouchani , R. Ahmad , and E. D. Rosen . 2021. IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis. J Clin Invest 131.","DOI":"10.1172\/JCI144888"},{"key":"2026020608174905000_2026.01.19.700051v1.36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006651"},{"key":"2026020608174905000_2026.01.19.700051v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-025-00549-2"},{"key":"2026020608174905000_2026.01.19.700051v1.38","doi-asserted-by":"crossref","first-page":"720765","DOI":"10.3389\/fimmu.2021.720765","article-title":"Proteomics Mapping of the ISGylation Landscape in Innate Immunity","volume":"12","year":"2021","journal-title":"Front Immunol"},{"key":"2026020608174905000_2026.01.19.700051v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0078-7"},{"key":"2026020608174905000_2026.01.19.700051v1.40","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.221713"},{"key":"2026020608174905000_2026.01.19.700051v1.41","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1318"},{"key":"2026020608174905000_2026.01.19.700051v1.42","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1002\/acr.20526","article-title":"Impact of obesity on functioning among women with systemic lupus erythematosus","volume":"63","year":"2011","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"2026020608174905000_2026.01.19.700051v1.43","doi-asserted-by":"publisher","DOI":"10.1002\/art.21400"},{"key":"2026020608174905000_2026.01.19.700051v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112708"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.19.700051","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T16:18:02Z","timestamp":1770394682000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.19.700051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":44,"URL":"https:\/\/doi.org\/10.64898\/2026.01.19.700051","relation":{},"subject":[],"published":{"date-parts":[[2026,1,21]]},"subtype":"preprint"}}