{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:04:16Z","timestamp":1793109856156,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin fibrosis. Altered metabolism has recently been described in autoimmune diseases and SSc. Itaconate is a product of the Krebs cycle intermediate cis-aconitate and is an immunomodulator. This work examines the role of the cell-permeable derivative of itaconate, 4-octyl itaconate (4-OI), in SSc. SSc and healthy dermal fibroblasts were exposed to 4-OI. The levels of collagen Nrf2-target genes and pro-inflammatory cytokines interleukin 6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) were determined. Levels of reactive oxygen species (ROS) as well as the gene expression of collagen and Cellular Communication Network Factor 2 (CCN2) were measured after transforming growth factor beta 1 (TGF-\u03b21) stimulation in the presence or absence of 4-OI. Wild-type or Nrf2-knockout (Nrf2-KO) mouse embryonic fibroblasts (MEFs) were also treated with 4-OI to determine the role of Nrf2 in 4-OI-mediated effects. 4-OI reduced the levels of collagen in SSc dermal fibroblasts. Incubation with 4-OI led to activation of Nrf2 and its target genes heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). 4-OI activated antioxidant response element (ARE)-dependent gene expression, reduced inflammatory cytokine release and reduced TGF-\u03b21-induced collagen and ROS production in dermal fibroblasts. The effects of 4-OI are dependent on Nrf2. The cell-permeable derivative of itaconate 4-OI is anti-fibrotic through upregulation of Nrf2 and could be a potential therapeutic option in an intractable disease.<\/jats:p>","DOI":"10.3390\/cells10082053","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T22:40:31Z","timestamp":1628635231000},"page":"2053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["The Cell-Permeable Derivative of the Immunoregulatory Metabolite Itaconate, 4-Octyl Itaconate, Is Anti-Fibrotic in Systemic Sclerosis"],"prefix":"10.3390","volume":"10","author":[{"given":"John","family":"Henderson","sequence":"first","affiliation":[{"name":"Applied Sciences, NorthuMbria University, Ellison Place, Newcastle Upon Tyne NE7 7XA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharadha","family":"Dayalan Naidu","sequence":"additional","affiliation":[{"name":"Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0316-9859","authenticated-orcid":false,"given":"Albena T.","family":"Dinkova-Kostova","sequence":"additional","affiliation":[{"name":"Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Przyborski","sequence":"additional","affiliation":[{"name":"Biosciences, Durham University, South Road, Durham DH1 3LE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Stratton","sequence":"additional","affiliation":[{"name":"Institute of Inflammation, University College London, Pond Street, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"O\u2032Reilly","sequence":"additional","affiliation":[{"name":"Biosciences, Durham University, South Road, Durham DH1 3LE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11926-020-00918-3","article-title":"Current and Potential New Targets in Systemic Sclerosis Therapy: A New Hope","volume":"22","author":"Hinchcliff","year":"2020","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/s41584-019-0184-z","article-title":"Emerging targets of disease-modifying therapy for systemic sclerosis","volume":"15","author":"Volkmann","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/s41422-020-0291-z","article-title":"Targeting immunometabolism as an anti-inflammatory strategy","volume":"30","year":"2020","journal-title":"Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/eji.202048690","article-title":"TLR7 endogenous ligands remodel glycolytic macrophages and trigger skin-to-joint crosstalk in psoriatic arthritis","volume":"51","author":"Umar","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/BF00172150","article-title":"Cloning and analysis of gene regulation of a novel LPS-inducible cDNA","volume":"41","author":"Lee","year":"1995","journal-title":"Immunogenetics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14274","DOI":"10.1074\/jbc.M115.685792","article-title":"Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels","volume":"291","author":"Cordes","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7820","DOI":"10.1073\/pnas.1218599110","article-title":"Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production","volume":"110","author":"Michelucci","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1084\/jem.20180118","article-title":"Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection","volume":"215","author":"Nair","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.immuni.2018.11.017","article-title":"The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons","volume":"50","author":"Daniels","year":"2019","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e54877","DOI":"10.7554\/eLife.54877","article-title":"Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response","volume":"9","author":"Sun","year":"2020","journal-title":"Elife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1002\/hep.31147","article-title":"IRG1\/Itaconate Activates Nrf2 in Hepatocytes to Protect Against Liver Ischemia-Reperfusion Injury","volume":"72","author":"Yi","year":"2020","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14026","DOI":"10.1111\/jcmm.16013","article-title":"Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis","volume":"24","author":"Henderson","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1158\/1940-6207.CAPR-14-0362","article-title":"Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans","volume":"8","author":"Knatko","year":"2015","journal-title":"Cancer Prev. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature25986","article-title":"Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1","volume":"556","author":"Mills","year":"2018","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1128\/MCB.24.16.7130-7139.2004","article-title":"Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2","volume":"24","author":"Kobayashi","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.trsl.2016.12.002","article-title":"Nrf2 exerts cell-autonomous antifibrotic effects: Compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative","volume":"183","author":"Wei","year":"2017","journal-title":"Transl. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10941","DOI":"10.1128\/MCB.24.24.10941-10953.2004","article-title":"Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex","volume":"24","author":"Zhang","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"He, F., Ru, X., and Wen, T. (2020). NRF2, a Transcription Factor for Stress Response and Beyond. Int. J. Mol. Sci, 21.","DOI":"10.3390\/ijms21134777"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41586-018-0052-z","article-title":"Electrophilic properties of itaconate and derivatives regulate the I\u03baB\u03b6\u2013ATF3 inflammatory axis","volume":"556","author":"Bambouskova","year":"2018","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.ajpath.2012.09.007","article-title":"Toll-Like Receptor 4 Signaling Augments Transforming Growth Factor-\u03b2 Responses: A Novel Mechanism for Maintaining and Amplifying Fibrosis in Scleroderma","volume":"182","author":"Bhattacharyya","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1038\/cti.2013.2","article-title":"Interleukin-6: A new therapeutic target in systemic sclerosis?","volume":"2","author":"Cant","year":"2013","journal-title":"Clin. Transl. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9952","DOI":"10.1074\/jbc.M113.545822","article-title":"Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-\u03b2 (TGF-\u03b2) signaling promoting SMAD3 activation and fibrosis via Gremlin protein","volume":"289","author":"Ciechomska","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/nrrheum.2014.137","article-title":"Transforming growth factor \u03b2--at the centre of systemic sclerosis","volume":"10","author":"Lafyatis","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13075-016-0929-x","article-title":"MicroRNAs in fibrosis: Opportunities and challenges","volume":"18","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/rheumatology\/key071","article-title":"Epigenetic modulation as a therapy in systemic sclerosis","volume":"58","year":"2019","journal-title":"Rheumatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1038\/ncomms6099","article-title":"A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes","volume":"5","author":"Kurinna","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13075-017-1331-z","article-title":"Mir-155 is overexpressed in systemic sclerosis fibroblasts and is required for NLRP3 inflammasome-mediated collagen synthesis during fibrosis","volume":"19","author":"Artlett","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5091","DOI":"10.1038\/s41467-019-13078-5","article-title":"4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects","volume":"10","author":"Liao","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10894","DOI":"10.1021\/jacs.9b11962","article-title":"Chemoproteomic Profiling of Itaconation by Bioorthogonal Probes in Inflammatory Macrophages","volume":"142","author":"Qin","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12929","DOI":"10.1096\/fj.201900887RR","article-title":"Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling","volume":"33","author":"Sun","year":"2019","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.cmet.2020.07.016","article-title":"The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation","volume":"32","author":"Hooftman","year":"2020","journal-title":"Cell Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"eabc1884","DOI":"10.1126\/sciimmunol.abc1884","article-title":"Itaconate controls the severity of pulmonary fibrosis","volume":"5","author":"Ogger","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1093\/rheumatology\/kew251","article-title":"Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: Another role for CXCL4?","volume":"55","author":"Cossu","year":"2016","journal-title":"Rheumatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.3389\/fimmu.2018.01896","article-title":"The Nrf2-Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma","volume":"9","author":"Kavian","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1002\/art.27443","article-title":"MicroRNA-29, a key regulator of collagen expression in systemic sclerosis","volume":"62","author":"Maurer","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jid.2017.08.024","article-title":"Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis","volume":"138","author":"Toyama","year":"2018","journal-title":"J. Investig. Dermatol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/2053\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:43:43Z","timestamp":1760165023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/2053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,10]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cells10082053"],"URL":"https:\/\/doi.org\/10.3390\/cells10082053","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,10]]}}}