{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:34:25Z","timestamp":1788406465727,"version":"build-2803163510"},"reference-count":25,"publisher":"Bioscientifica","issue":"5","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>In recent years, EZH2 inhibitors have shown potential therapeutic value in certain hematological malignancies and solid tumors. However, the role and mechanisms of EZH2 in pancreatic neuroendocrine neoplasms (pNENs) remain unclear. This study investigated the effects and mechanism of the EZH2 inhibitor GSK126 on pNENs. Public database analysis revealed that increased EZH2 expression correlates with poor prognosis in pNEN patients. We found that EZH2 is significantly upregulated in pNEN tissues and cell lines, and its knockdown or treatment with GSK126 inhibits proliferation and induces ferroptosis in vitro. In vivo, EZH2 knockdown or GSK126 treatment suppressed subcutaneous tumor growth in nude mice. Mechanistic studies showed that GSK126 induces ferroptosis by inhibiting the PI3K\/AKT\/mTOR pathway. In addition, GSK126 upregulated HMGCS1, a gene linked to ferroptosis. HMGCS1 may act as an oncogene by activating the PI3K\/AKT\/mTOR pathway, and the knockdown of HMGCS1 can enhance GSK126-induced ferroptosis and the inhibitory effect of GSK126 on the PI3K\/AKT\/mTOR pathway. Furthermore, combining GSK126 with everolimus, an mTOR inhibitor used clinically for pNENs, more effectively inhibited cell proliferation and tumor growth. In summary, our findings reveal that the EZH2 inhibitor GSK126 induces ferroptosis by inhibiting the PI3K\/AKT\/mTOR pathway, suppressing pNENs progression, and HMGCS1 may mediate resistance to EZH2 inhibitors, offering new insights into pNEN treatment.<\/jats:p>","DOI":"10.1530\/erc-25-0478","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T16:54:06Z","timestamp":1776790446000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":3,"title":["<i>HMGCS1<\/i>\n                    as a potential mediator of resistance to EZH2 inhibition via ferroptosis mediated by PI3K\/AKT\/mTOR pathway in the pancreatic neuroendocrine neoplasms"],"prefix":"10.1530","volume":"33","author":[{"given":"Na","family":"He","sequence":"first","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Xu","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Yan","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Hu","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7822-7297","authenticated-orcid":true,"given":"Jianan","family":"Bai","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyan","family":"Xue","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Hu","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xintong","family":"Lu","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7731-9857","authenticated-orcid":true,"given":"Mujie","family":"Ye","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2408-7908","authenticated-orcid":true,"given":"Qiyun","family":"Tang","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"2026070909462963100_bib1","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s40618-022-01985-2","article-title":"The incidence, prevalence, and survival analysis of pancreatic neuroendocrine tumors in the United States","volume":"46","author":"Liu","year":"2022","journal-title":"J Endocrinol Investig"},{"key":"2026070909462963100_bib2","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.7150\/ijbs.96831","article-title":"Hypoxic tumor-derived exosomal miR-4488 induces macrophage M2 polarization to promote liver metastasis of pancreatic neuroendocrine neoplasm through RTN3\/FABP5 mediated fatty acid oxidation","volume":"20","author":"Lu","year":"2024","journal-title":"Int J Biol Sci"},{"key":"2026070909462963100_bib3","doi-asserted-by":"crossref","first-page":"71699","DOI":"10.18632\/oncotarget.17599","article-title":"A nation-wide retrospective epidemiological study of gastroenteropancreatic neuroendocrine neoplasms in China","volume":"8","author":"Fan","year":"2017","journal-title":"Oncotarget"},{"key":"2026070909462963100_bib4","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s10120-020-01046-8","article-title":"Trends of incidence and prognosis of gastric neuroendocrine neoplasms: a study based on SEER and our multicenter research","volume":"23","author":"Hu","year":"2020","journal-title":"Gastric Cancer"},{"key":"2026070909462963100_bib5","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1186\/s12967-023-04578-6","article-title":"ALKBH5 enhances lipid metabolism reprogramming by increasing stability of FABP5 to promote pancreatic neuroendocrine neoplasms progression in an m6A-IGF2BP2-dependent manner","volume":"21","author":"Chen","year":"2023","journal-title":"J Transl Med"},{"key":"2026070909462963100_bib6","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s42003-020-01479-y","article-title":"Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression","volume":"3","author":"Di Domenico","year":"2020","journal-title":"Commun Biol"},{"key":"2026070909462963100_bib7","doi-asserted-by":"crossref","first-page":"R315","DOI":"10.1530\/ERC-17-0012","article-title":"Genetic and epigenetic drivers of neuroendocrine tumours (NET)","volume":"24","author":"Di Domenico","year":"2017","journal-title":"Endocr Relat Cancer"},{"key":"2026070909462963100_bib8","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nature09784","article-title":"The polycomb complex PRC2 and its mark in life","volume":"469","author":"Margueron","year":"2011","journal-title":"Nature"},{"key":"2026070909462963100_bib9","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s12032-023-02025-6","article-title":"The roles of EZH2 in cancer and its inhibitors","volume":"40","author":"Liu","year":"2023","journal-title":"Med Oncol"},{"key":"2026070909462963100_bib10","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1111\/cas.16186","article-title":"EZH2 suppresses ferroptosis in hepatocellular carcinoma and reduces sorafenib sensitivity through epigenetic regulation of TFR2","volume":"115","author":"Lai","year":"2024","journal-title":"Cancer Sci"},{"key":"2026070909462963100_bib11","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.bbrc.2018.12.039","article-title":"Lipid storage and lipophagy regulates ferroptosis","volume":"508","author":"Bai","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"key":"2026070909462963100_bib12","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026070909462963100_bib13","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13045-020-00937-8","article-title":"EZH2: a novel target for cancer treatment","volume":"13","author":"Duan","year":"2020","journal-title":"J Hematol Oncol"},{"key":"2026070909462963100_bib14","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1177\/0022034517746987","article-title":"EZH2 impairs human dental pulp cell mineralization via the Wnt\/\u03b2-Catenin pathway","volume":"97","author":"Li","year":"2018","journal-title":"J Dent Res"},{"key":"2026070909462963100_bib15","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2021.153706","article-title":"Combination of curcumin with N-n-butyl haloperidol iodide inhibits hepatocellular carcinoma malignant proliferation by downregulating enhancer of zeste homolog 2 (EZH2) - lncRNA H19 to silence Wnt\/\u03b2-catenin signaling","volume":"91","author":"Khan","year":"2021","journal-title":"Phytomedicine: Int J Phytotherapy Phytopharmacology"},{"key":"2026070909462963100_bib16","doi-asserted-by":"crossref","first-page":"4118","DOI":"10.1038\/onc.2011.118","article-title":"MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes","volume":"30","author":"Fujii","year":"2011","journal-title":"Oncogene"},{"key":"2026070909462963100_bib17","doi-asserted-by":"crossref","first-page":"4375","DOI":"10.1172\/JCI80325","article-title":"Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma","volume":"125","author":"Kikuchi","year":"2015","journal-title":"J Clin Investig"},{"key":"2026070909462963100_bib18","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.26218","article-title":"Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the pediatric preclinical testing program","volume":"64","author":"Kurmasheva","year":"2017","journal-title":"Pediatr Blood Cancer"},{"key":"2026070909462963100_bib19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1042\/CS20231478","article-title":"Inhibition of the histone methyltransferase EZH2 induces vascular stiffness","volume":"138","author":"Ibarrola","year":"2024","journal-title":"Clin Sci"},{"key":"2026070909462963100_bib20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13148-023-01430-y","article-title":"Azithromycin attenuates wheezing after pulmonary inflammation through inhibiting histone H3K27me3 hypermethylation mediated by EZH2","volume":"15","author":"Wu","year":"2023","journal-title":"Clin Epigenet"},{"key":"2026070909462963100_bib21","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1002\/tcr.201800091","article-title":"Six years (2012-2018) of researches on catalytic EZH2 inhibitors: the boom of the 2-Pyridone compounds","volume":"18","author":"Fioravanti","year":"2018","journal-title":"Chem Rec"},{"key":"2026070909462963100_bib22","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1172\/JCI99760","article-title":"Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy","volume":"128","author":"Goswami","year":"2018","journal-title":"J Clin Investig"},{"key":"2026070909462963100_bib23","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.neo.2021.06.007","article-title":"EZH2i EPZ-6438 and HDACi vorinostat synergize with ONC201\/TIC10 to activate integrated stress response, DR5, reduce H3K27 methylation, ClpX and promote apoptosis of multiple tumor types including DIPG","volume":"23","author":"Zhang","year":"2021","journal-title":"Neoplasia"},{"key":"2026070909462963100_bib24","first-page":"1","article-title":"Prognostic model and immune infiltration of ferroptosis subcluster-related modular genes in gastric cancer","volume":"2022","author":"Deng","year":"2022","journal-title":"J Oncol"},{"key":"2026070909462963100_bib25","first-page":"1","article-title":"CIRBP regulates pancreatic cancer cell ferroptosis and growth by directly binding to p53","volume":"2022","author":"Gao","year":"2022","journal-title":"J Immunol Res"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/33\/5\/ERC-25-0478.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/33\/5\/ERC-25-0478.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0478\/506760\/erc-25-0478.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0478\/506760\/erc-25-0478.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:46:36Z","timestamp":1783604796000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/33\/5\/e250478\/75596\/HMGCS1-as-a-potential-mediator-of-resistance-to"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":25,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-25-0478","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2026,4,21]]},"article-number":"e250478"}}