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In addition, they displayed a multifaceted pathological phenotype featuring increased apoptosis\/pyroptosis, oxidative stress, glycolysis, and acylcarnitine levels, but decreased glutamine uptake, BCAT1 expression, branched chain amino acid catabolism, oxidative phosphorylation, \u03b2\u2010oxidation, and NAD(P)H\u2010dependent oxidoreductase activity. Furthermore, expression of genes involved in mitochondrial biogenesis and respiratory chain complexes II\u2013V was diminished in <jats:italic>ISG15<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> cells. Defective mitochondrial respiration was restored by transduction with wild\u2010type ISG15, but only partially by a conjugation\u2010deficient variant, suggesting that some ISG15 functions in mitochondrial respiration require ISGylation to cellular targets. Treatment with itaconate, dimethyl\u2010itaconate, 4\u2010octyl\u2010itaconate, and the JAK1\/2 inhibitor ruxolitinib ameliorated increased inflammation, propensity for cell death, and oxidative stress. Furthermore, the treatments greatly improved mitochondria\u2010related gene expression, BCAT1 levels, redox balance, and intracellular and extracellular ATP levels. However, efficacy differed among the compounds according to read\u2010out and cell type, suggesting that their effects on cellular targets are not identical. Indeed, only itaconates increased expression of anti\u2010oxidant genes <jats:italic>NFE2L2, HMOX1<\/jats:italic>, and <jats:italic>GPX7<\/jats:italic>, and dimethyl\u2010itaconate improved redox balance the most. Even though itaconate treatments normalized the elevated expression of interferon\u2010stimulated genes, <jats:italic>ISG15<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> macrophages maintained their reduced susceptibility to influenza virus infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings expand the cellular phenotype of human ISG15 deficiency and reveal the importance of ISG15 for regulating oxidative stress, branched chain amino acid metabolism, and mitochondrial function in humans. The results validate ruxolitinib as treatment for ISG15 deficiency and suggest itaconate\u2010based medications as additional therapeutics for this rare disorder.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.931","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T16:26:22Z","timestamp":1658075182000},"source":"Crossref","is-referenced-by-count":42,"title":["ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0340-9648","authenticated-orcid":false,"given":"Syed Fakhar\u2010ul\u2010Hassnain","family":"Waqas","sequence":"first","affiliation":[{"name":"Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research  Hannover Germany"},{"name":"Research Group Biomarkers for Infectious Diseases Helmholtz Centre for Infection Research  Braunschweig 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