{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:52:10Z","timestamp":1791471130568,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W023806\/1"],"award-info":[{"award-number":["MR\/W023806\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"award":["MR\/W023806\/1"],"award-info":[{"award-number":["MR\/W023806\/1"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Glioblastoma is a primary aggressive brain tumor, with an average survival rate of ~14.6 months. The low therapeutic benefit of current treatments is in part due to glioblastoma-initiating cells hijacking microglia\/macrophages to support tumor growth, prompting the development of multitargeted therapeutic approaches. One such therapeutic target is transcription factor Nrf2. High Nrf2 activity is associated with high-grade tumors, and high Nrf2 levels in microglia\/macrophages lead to polarization toward an immunosuppressive profile, supporting glioblastoma progression and therapy resistance. Interestingly, however, sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables and a potent Nrf2 activator, has anti-carcinogenic effects in multiple animal models. Methods: We utilized the zebrafish glioblastoma initiation model of human AKT1 overexpression in neuronal progenitors to capture the intermediate progenitor-cell-like state of glioblastoma-initiating\/pre-neoplastic cells and evaluated the therapeutic potential of SFN and VVD130037, an Nrf2 inhibitor currently in clinical trials. Results: Initial findings suggest that SFN, individually and in combination with VVD130037, had the potential to decrease the levels of AKT1. Surprisingly, VVD130037 tended to increase AKT1. The pAKT1 levels also increased in Nrf2-deficient human cells. Moreover, failure to activate Nrf2 in neural progenitors in response to SFN, while a preliminary observation that warrants further investigation, suggests that the decrease in AKT1 was not potentially mediated by Nrf2 activation. The combined effect of SFN and VVD130037 on AKT1 was particularly strong in irf8-\/- mutant larvae, which lack a microglia\/macrophage population, indicating the existence of a non-tumorigenic cell population(s) sensitive to changes in Nrf2 activity. Conclusions: AKT1 inhibition in glioblastoma-initiating cells by the phytochemical SFN, combined with Nrf2 inhibition in the surrounding cells, may impede glioma progression.<\/jats:p>","DOI":"10.3390\/nu18162694","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T12:09:32Z","timestamp":1787054972000},"page":"2694","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sulforaphane Decreases the Burden of AKT1-Expressing Pre-Neoplastic Cells in a Zebrafish Model of Glioblastoma Initiation"],"prefix":"10.3390","volume":"18","author":[{"given":"Manana","family":"Kutsia","sequence":"first","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH8 9YL, UK"},{"name":"Cancer Research UK Scotland Centre, Edinburgh EH4 2XR, UK"},{"name":"Department of Physiology, College of Medicine, Korea University, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver J.","family":"Read","sequence":"additional","affiliation":[{"name":"Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharadha","family":"Dayalan Naidu","sequence":"additional","affiliation":[{"name":"Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, 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":"Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK"},{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Sieger","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH8 9YL, UK"},{"name":"Cancer Research UK Scotland Centre, Edinburgh EH4 2XR, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 System: A Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104217","DOI":"10.1016\/j.redox.2026.104217","article-title":"NRF2 as a guardian of health: From an ancient survival pathway to a modern therapeutic target","volume":"94","author":"Tenreiro","year":"2026","journal-title":"Redox Biol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cucci, M.A., Grattarola, M., Monge, C., Roetto, A., Barrera, G., Caputo, E., Dianzani, C., and Pizzimenti, S. (2023). Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma. Antioxidants, 12.","DOI":"10.3390\/antiox12061313"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"152203","DOI":"10.1016\/j.acthis.2024.152203","article-title":"Nrf2: A critical participant in regulation of apoptosis, ferroptosis, and autophagy in gastric cancer","volume":"126","author":"Tang","year":"2024","journal-title":"Acta Histochem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, G., Zhong, K., Wang, Z., Zhang, Z., Tang, X., Tong, A., and Zhou, L. (2022). Tumor-associated microglia and macrophages in glioblastoma: From basic insights to therapeutic opportunities. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.964898"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7473","DOI":"10.1038\/s41388-019-0956-6","article-title":"Nrf2 and SQSTM1\/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma","volume":"38","author":"Leinonen","year":"2019","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1038\/s41388-025-03560-4","article-title":"NRF2 immunobiology in cancer: Implications for immunotherapy and therapeutic targeting","volume":"44","author":"Panda","year":"2025","journal-title":"Oncogene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"142","DOI":"10.14348\/molcells.2023.2183","article-title":"Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment","volume":"46","author":"Feng","year":"2023","journal-title":"Mol. Cells"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Asif Ali, M., Khan, N., Kaleem, N., Ahmad, W., Alharethi, S.H., Alharbi, B., Alhassan, H.H., Al-Enazi, M.M., Razis, A.F.A., and Modu, B. (2023). Anticancer properties of sulforaphane: Current insights at the molecular level. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1168321"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.3171\/2016.8.JNS161197","article-title":"Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways","volume":"127","author":"Wang","year":"2017","journal-title":"J. Neurosurg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16016","DOI":"10.1038\/s41598-024-65455-w","article-title":"Antitumor and antimetastatic effects of dietary sulforaphane in a triple-negative breast cancer models","volume":"14","author":"Pogorzelska","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"217145","DOI":"10.1016\/j.canlet.2024.217145","article-title":"Sulforaphane suppresses bladder cancer metastasis via blocking actin nucleation-mediated pseudopodia formation","volume":"601","author":"Huang","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhang, F., Wan, X., Zhan, J., Shen, M., and Li, R. (2024). Sulforaphane inhibits the growth of prostate cancer by regulating the microRNA-3919\/DJ-1 axis. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1361152"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.freeradbiomed.2026.03.029","article-title":"Therapeutic potential of isothiocyanates by targeting the NRF2 pathway","volume":"248","author":"Cazalla","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1700965","DOI":"10.1002\/mnfr.201700965","article-title":"Isothiocyanates: Translating the Power of Plants to People","volume":"62","author":"Palliyaguru","year":"2018","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fahey, J.W., and Liu, H. (2026). Sulforaphane Synergies with Phytochemicals and Pharmaceuticals: Implications for Healthspan. Medicines, 13.","DOI":"10.3390\/medicines13020016"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1158\/2159-8290.CD-25-1187","article-title":"A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth","volume":"16","author":"Roy","year":"2026","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103885","DOI":"10.1016\/j.redox.2025.103885","article-title":"Bidirectional regulation of KEAP1 BTB domain-based sensor activity","volume":"87","author":"Suzuki","year":"2025","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"153062","DOI":"10.1016\/j.phymed.2019.153062","article-title":"The isothiocyanate sulforaphane inhibits mTOR in an NRF2-independent manner","volume":"86","author":"Zhang","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.stem.2009.03.014","article-title":"Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens","volume":"4","author":"Pollard","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1073\/pnas.051632198","article-title":"Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups","volume":"98","author":"Massiah","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mazzolini, J., Chia, K., and Sieger, D. (2018). Isolation and RNA Extraction of Neurons, Macrophages and Microglia from Larval Zebrafish Brains. J. Vis. Exp., 57431.","DOI":"10.3791\/57431-v"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e31918","DOI":"10.7554\/eLife.31918","article-title":"Tumor initiating cells induce Cxcr4-mediated infiltration of pro-tumoral macrophages into the brain","volume":"7","author":"Chia","year":"2018","journal-title":"eLife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7066","DOI":"10.1038\/ncomms8066","article-title":"Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2","volume":"6","author":"Bell","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e46912","DOI":"10.7554\/eLife.46912","article-title":"Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation","volume":"8","author":"Chia","year":"2019","journal-title":"eLife"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"G\u00f3rska-Jakubowska, S., Wu, Y., Tur\u0142o, J., and Xu, B. (2025). Critical Review on the Anti-Tumor Activity of Bioactive Compounds from Edible and Medicinal Mushrooms over the Last Five Years. Nutrients, 17.","DOI":"10.3390\/nu17111887"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"217429","DOI":"10.1016\/j.canlet.2024.217429","article-title":"Sulforaphane potentiates the efficacy of chemoradiotherapy in glioblastoma by selectively targeting thioredoxin reductase 1","volume":"611","author":"Ge","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"680","DOI":"10.4049\/jimmunol.181.1.680","article-title":"The transcription factor Nrf2 is a therapeutic target against brain inflammation","volume":"181","author":"Innamorato","year":"2008","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15550","DOI":"10.1073\/pnas.1416940111","article-title":"Sulforaphane treatment of autism spectrum disorder (ASD)","volume":"111","author":"Singh","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.bbrc.2012.08.107","article-title":"Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway","volume":"426","author":"Lee","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5767","DOI":"10.1158\/0008-5472.CAN-04-1326","article-title":"A novel mechanism of chemoprotection by sulforaphane: Inhibition of histone deacetylase","volume":"64","author":"Myzak","year":"2004","journal-title":"Cancer Res."},{"key":"ref_32","first-page":"227","article-title":"Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects","volume":"232","author":"Myzak","year":"2007","journal-title":"Exp. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1021\/acschembio.6b01014","article-title":"Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells","volume":"12","author":"Iaconelli","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1158\/1535-7163.MCT-06-0404","article-title":"Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells","volume":"6","author":"Chaudhuri","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.bbrc.2015.08.049","article-title":"Sulforaphane induces apoptosis in adipocytes via Akt\/p70s6k1\/Bad inhibition and ERK activation","volume":"465","author":"Yao","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.lfs.2018.10.034","article-title":"Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative breast cancer cells","volume":"213","author":"Yang","year":"2018","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1080\/01635581.2022.2156555","article-title":"Sulforaphane Suppresses MCF-7 Breast Cancer Cells Growth via miR-19\/PTEN Axis to Antagonize the Effect of Butyl Benzyl Phthalate","volume":"75","author":"Cao","year":"2023","journal-title":"Nutr. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3732","DOI":"10.1002\/ptr.7069","article-title":"Regulation of microRNA-21 expression by natural products in cancer","volume":"35","author":"Shakeri","year":"2021","journal-title":"Phytother. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/16\/2694\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T12:15:31Z","timestamp":1787055331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/16\/2694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":38,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18162694"],"URL":"https:\/\/doi.org\/10.3390\/nu18162694","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]}}}