{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:24:03Z","timestamp":1781832243507,"version":"3.54.5"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Joint Fund of Natural Science Foundation of Jilin Province"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Interleukin-1 receptor-associated kinase 1 (IRAK1), a pivotal mediator in innate immunity and inflammatory processes, exhibits constitutive activation across various cancers. Our study highlights the significant role of IRAK1 in gastric cancer progression. We observed elevated IRAK1 expression in both gastric cancer tissues and cells, which correlates with malignant phenotypes, including heightened proliferation, colony formation, and migratory capacity in normal gastric cells upon IRAK1 overexpression. Silencing IRAK1 genetically in gastric cancer cells effectively suppressed these oncogenic traits. Notably, we found that gastric cancer cells display marked sensitivity to IRAK1\/4 inhibitor and pacritinib, the latter targeting JAK2 and IRAK1 specifically, over the pan-JAK inhibitor tofacitinib. In vivo experiments using a xenograft mouse model demonstrated the efficacy of pacritinib in arresting gastric cancer growth without eliciting significant systemic toxicity. Immunohistochemical analyses further confirmed pacritinib\u2019s ability to attenuate tumor progression by inhibiting IRAK1 activity. Collectively, our results underscore IRAK1 as a promising therapeutic target in gastric cancer. Furthermore, the pharmacological blockade of IRAK1 by pacritinib, an established drug for myelofibrosis and severe thrombocytopenia treatment, holds potential for repurposing in gastric cancer therapy.<\/jats:p>","DOI":"10.1007\/s12672-025-03658-x","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T15:47:59Z","timestamp":1760456879000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interleukin-1 receptor-associated kinase-1 is a therapeutic target for gastric cancer"],"prefix":"10.1007","volume":"16","author":[{"given":"Hui","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8785-3848","authenticated-orcid":false,"given":"Xiaohua","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"3658_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-024-01494-6","author":"Y Li","year":"2024","unstructured":"Li Y, Hahn AI, Laszkowska M, Jiang F, Zauber AG, Leung WK. Global burden of young-onset gastric cancer: a systematic trend analysis of the global burden of disease study 2019. Gastric Cancer. 2024. https:\/\/doi.org\/10.1007\/s10120-024-01494-6.","journal-title":"Gastric Cancer"},{"key":"3658_CR2","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1007\/s10555-020-09925-3","volume":"39","author":"RE Sexton","year":"2020","unstructured":"Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev. 2020;39:1179\u2013203. https:\/\/doi.org\/10.1007\/s10555-020-09925-3.","journal-title":"Cancer Metastasis Rev"},{"key":"3658_CR3","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","volume":"376","author":"YJ Bang","year":"2010","unstructured":"Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK, To GATI. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687\u201397. https:\/\/doi.org\/10.1016\/S0140-6736(10)61121-X.","journal-title":"Lancet"},{"key":"3658_CR4","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1159\/000537779","volume":"17","author":"A Horiuchi","year":"2024","unstructured":"Horiuchi A, Akehi S, Fujiwara Y, Kawaharada S, Anai T. A case of long-term survival with recurrent liver metastases from gastric cancer treated with nivolumab. Case Rep Oncol. 2024;17:438\u201346. https:\/\/doi.org\/10.1159\/000537779.","journal-title":"Case Rep Oncol"},{"key":"3658_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102461","volume":"19","author":"LC Su","year":"2020","unstructured":"Su LC, Xu WD, Huang AF. IRAK family in inflammatory autoimmune diseases. Autoimmun Rev. 2020;19:102461. https:\/\/doi.org\/10.1016\/j.autrev.2020.102461.","journal-title":"Autoimmun Rev"},{"key":"3658_CR6","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1097\/MOH.0000000000000693","volume":"29","author":"J Bennett","year":"2022","unstructured":"Bennett J, Starczynowski DT. IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies. Curr Opin Hematol. 2022;29:8\u201319. https:\/\/doi.org\/10.1097\/MOH.0000000000000693.","journal-title":"Curr Opin Hematol"},{"key":"3658_CR7","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1158\/0008-5472.CAN-20-2125","volume":"81","author":"L Liu","year":"2021","unstructured":"Liu L, Liu S, Deng P, Liang Y, Xiao R, Tang LQ, et al. Targeting the IRAK1-S100A9 axis overcomes resistance to Paclitaxel in nasopharyngeal carcinoma. Cancer Res. 2021;81:1413\u201325. https:\/\/doi.org\/10.1158\/0008-5472.CAN-20-2125.","journal-title":"Cancer Res"},{"key":"3658_CR8","doi-asserted-by":"publisher","first-page":"8746","DOI":"10.1038\/ncomms9746","volume":"6","author":"ZN Wee","year":"2015","unstructured":"Wee ZN, Yatim SM, Kohlbauer VK, Feng M, Goh JY, Bao Y, Lee PL, Zhang S, Wang PP, Lim E, Tam WL, Cai Y, Ditzel HJ, Hoon DS, Tan EY, Yu Q. IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to Paclitaxel. Nat Commun. 2015;6:8746. https:\/\/doi.org\/10.1038\/ncomms9746.","journal-title":"Nat Commun"},{"key":"3658_CR9","first-page":"8096","volume":"7","author":"X Zhang","year":"2014","unstructured":"Zhang X, Dang Y, Li P, Rong M, Chen G. Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study. Int J Clin Exp Pathol. 2014;7:8096\u2013104.","journal-title":"Int J Clin Exp Pathol"},{"key":"3658_CR10","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.991368","volume":"12","author":"U Schagdarsurengin","year":"2022","unstructured":"Schagdarsurengin U, Breiding V, Loose M, Wagenlehner F, Dansranjav T. Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer. Front Oncol. 2022;12:991368. https:\/\/doi.org\/10.3389\/fonc.2022.991368.","journal-title":"Front Oncol"},{"key":"3658_CR11","doi-asserted-by":"publisher","first-page":"2374","DOI":"10.1038\/s41375-018-0112-2","volume":"32","author":"MM Hosseini","year":"2018","unstructured":"Hosseini MM, Kurtz SE, Abdelhamed S, Mahmood S, Davare MA, Kaempf A, Elferich J, McDermott JE, Liu T, Payne SH, Shinde U, Rodland KD, Mori M, Druker BJ, Singer JW, Agarwal A. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia. 2018;32:2374\u201387. https:\/\/doi.org\/10.1038\/s41375-018-0112-2.","journal-title":"Leukemia"},{"key":"3658_CR12","doi-asserted-by":"publisher","first-page":"6209","DOI":"10.1158\/0008-5472.CAN-12-0337","volume":"72","author":"R Srivastava","year":"2012","unstructured":"Srivastava R, Geng D, Liu Y, Zheng L, Li Z, Joseph MA, et al. Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4. Cancer Res. 2012;72:6209\u201316. https:\/\/doi.org\/10.1158\/0008-5472.CAN-12-0337.","journal-title":"Cancer Res"},{"key":"3658_CR13","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.904959","volume":"9","author":"M Liu","year":"2022","unstructured":"Liu M, Que Y, Hong Y, Zhang L, Zhang X, Zhang Y. A pan-cancer analysis of IRAK1 expression and their association with immunotherapy response. 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Pacritinib to inhibit JAK\/STAT signaling in refractory metastatic colon and rectal cancer. J Gastrointest Oncol. 2017;8:985\u20139. https:\/\/doi.org\/10.21037\/jgo.2017.08.16.","journal-title":"J Gastrointest Oncol"},{"key":"3658_CR20","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.yexcr.2016.05.008","volume":"344","author":"N Ochi","year":"2016","unstructured":"Ochi N, Isozaki H, Takeyama M, Singer JW, Yamane H, Honda Y, Kiura K, Takigawa N. Synergistic effect of Pacritinib with erlotinib on JAK2-mediated resistance in epidermal Gowth factor receptor mutation-positive non-small cell lung cancer. Exp Cell Res. 2016;344:194\u2013200. https:\/\/doi.org\/10.1016\/j.yexcr.2016.05.008.","journal-title":"Exp Cell Res"},{"key":"3658_CR21","doi-asserted-by":"publisher","first-page":"7570","DOI":"10.1002\/jcb.27067","volume":"119","author":"R Ranjbar","year":"2018","unstructured":"Ranjbar R, Hesari A, Ghasemi F, Sahebkar A. Expression of micrornas and IRAK1 pathway genes are altered in gastric cancer patients with Helicobacter pylori infection. J Cell Biochem. 2018;119:7570\u20136. https:\/\/doi.org\/10.1002\/jcb.27067.","journal-title":"J Cell Biochem"},{"key":"3658_CR22","doi-asserted-by":"publisher","first-page":"2332","DOI":"10.1158\/0008-5472.CAN-17-2445","volume":"78","author":"BY Cheng","year":"2018","unstructured":"Cheng BY, Lau EY, Leung HW, Leung CO, Ho NP, Gurung S, et al. IRAK1 augments cancer stemness and drug resistance via the AP-1\/AKR1B10 signaling cascade in hepatocellular carcinoma. Cancer Res. 2018;78:2332\u201342. https:\/\/doi.org\/10.1158\/0008-5472.CAN-17-2445.","journal-title":"Cancer Res"},{"key":"3658_CR23","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41419-023-05732-0","volume":"14","author":"J Li","year":"2023","unstructured":"Li J, Sun Y, Zhao X, Ma Y, Xie Y, Liu S, Hui B, Shi X, Sun X, Zhang X. Radiation induces IRAK1 expression to promote radioresistance by suppressing autophagic cell death via decreasing the ubiquitination of PRDX1 in glioma cells. Cell Death Dis. 2023;14:259. https:\/\/doi.org\/10.1038\/s41419-023-05732-0.","journal-title":"Cell Death Dis"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-03658-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-025-03658-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-03658-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T02:17:29Z","timestamp":1760494649000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-025-03658-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3658"],"URL":"https:\/\/doi.org\/10.1007\/s12672-025-03658-x","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]},"assertion":[{"value":"13 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animal experiments were approved by the Institutional Animal Care and Use Committee of 964th Hospital of People\u2019s Liberation Army Joint Logistic Support Force (IACUC approval number 2022826), and all procedures were conducted in accordance with institutional and national guidelines. The maximal tumor size permitted by the ethics committee was 1800\u00a0mm\u00b3. We confirm that the tumor burden in all animals remained below this limit throughout the study.The use of human tissue specimens in this study was approved by the Institutional Review Board of the 964th Hospital of the People\u2019s Liberation Army Joint Logistic Support Force (Approval No.: CYXRMYYEC20230001). All procedures involving human participants were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent for tissue collection and use in research was obtained by the Department of Tissue Repository of the 964th Hospital of the People\u2019s Liberation Army Joint Logistic Support Force.Informed consent for the use of human tissue specimens was obtained by the Department of Tissue Repository at the 964th Hospital of the People\u2019s Liberation Army Joint Logistic Support Force, in accordance with institutional ethical regulations (IRB approval number SJC0616B).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and\u00a0consent to participate"}},{"value":"All authors have reviewed the final version of the manuscript and consent to its publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1882"}}