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However, identifying responsive tumor subpopulations remains a major obstacle in developing metabolism-targeted therapies, as metabolic vulnerabilities vary among cancers with different oncogene expression profiles. Therefore, elucidating the association between oncogene expression and metabolic characteristics could enable more precise metabolic interventions in clinical settings. Using pharmacological approaches, we demonstrate that VRK2-deficient pancreatic cancer (PC) cells exhibit heightened vulnerability to glutathione (GSH) metabolic pathway inhibition. This susceptibility stems from reduced basal GSH levels caused by impaired plasma membrane expression of SLC7A11. Mechanistically, we reveal that VRK2 inhibition disrupts endoplasmic reticulum (ER)-to-Golgi trafficking of SLC7A11, consequently diminishing GSH biosynthesis and predisposing PC cells to ferroptosis. Collectively, our findings establish a novel link between the oncogene VRK2 and GSH synthesis metabolism, providing a molecular basis for developing stratified metabolic therapies for PC patients.<\/jats:p>","DOI":"10.1038\/s41419-026-08573-9","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T23:14:11Z","timestamp":1773962051000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1908-5054","authenticated-orcid":false,"given":"Sisi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1254-0632","authenticated-orcid":false,"given":"Xiaowei","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuhai","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3751-4622","authenticated-orcid":false,"given":"Bin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4563-6778","authenticated-orcid":false,"given":"Hengqing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5931-0094","authenticated-orcid":false,"given":"Zhiyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"8573_CR1","first-page":"7","volume":"69","author":"RL Siegel","year":"2019","unstructured":"Siegel RL, Miller KD, Jemal A. 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Informed consent was obtained from the patients, and the study protocol was approved by the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine (Permit number: 2024-1360).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"325"}}