Targeting Mevalonate Pathway Enhances the efficacy of 5-Fluorouracil by regulating pyroptosis

Targeting Mevalonate Pathway Enhances the efficacy of 5-Fluorouracil by regulating pyroptosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Targeting Mevalonate Pathway Enhances the efficacy of 5-Fluorouracil by regulating pyroptosis Zongrui Xing, Yong Ma, Xiangyan Jiang, Huiguo Qing, Yuxia Wu, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5024083/v2 This work is licensed under a CC BY 4.0 License Archived Versions: Posted Version 2 posted You are reading this latest preprint version Abstract The 5-fluorouracil (5-FU)-based chemotherapy regimen is a primary strategy for treating pancreatic cancer (PC).However, challenges related to 5-FU resistance persist. Investigating the mechanisms of 5-FU resistance and identifying a clinically viable therapeutic strategy are crucial for improving the prognosis of PC. Here, through clinical samples analysis, we found that the expression of 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR),the rate-limiting enzyme in mevalonate metabolism, is negatively correlated with the efficacy of 5-FU treatment. There is a significant correlation between HMGCR and the pyroptosis marker Gasdermin D (GSDMD),and the HMGCR inhibitor simvastatin can significantly inhibit the activation of pyroptosis signaling. The exogenous addition of geranylgeranyl pyrophosphate (GGPP),a key metabolite of the mevalonate pathway, can significantly reduce sensitivity to 5-FU,and simvastatin combined with 5-FU demonstrates a strong synergistic effect. Furthermore, in organoid models and genetically engineered mice with spontaneous PC, the combination of simvastatin and 5-FU significantly inhibits tumor growth. In conclusion, our study reveals the critical role of the mevalonate pathway in 5-FU resistance and proposes a clinically feasible combination therapy strategy. 5-fluorouracil mevalonate pathway pyroptosis pancreatic cancer chemoresistance Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx RevisedSupplementaryMaterials.docx SupplementaryFigure1.tif Cite Share Download PDF Archived Versions: Posted Version 2 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5024083","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[{"code":2,"date":"2024-11-05 19:39:15","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"medical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"medo","sideBox":"Learn more about [Medical Oncology](https://www.springer.com/journal/12032)","snPcode":"12032","submissionUrl":"https://submission.nature.com/new-submission/12032/3","title":"Medical 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Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"5-fluorouracil, mevalonate pathway, pyroptosis, pancreatic cancer, chemoresistance","lastPublishedDoi":"10.21203/rs.3.rs-5024083/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5024083/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The 5-fluorouracil (5-FU)-based chemotherapy regimen is a primary strategy for treating pancreatic cancer (PC).However, challenges related to 5-FU resistance persist. Investigating the mechanisms of 5-FU resistance and identifying a clinically viable therapeutic strategy are crucial for improving the prognosis of PC. Here, through clinical samples analysis, we found that the expression of 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR),the rate-limiting enzyme in mevalonate metabolism, is negatively correlated with the efficacy of 5-FU treatment. There is a significant correlation between HMGCR and the pyroptosis marker Gasdermin D (GSDMD),and the HMGCR inhibitor simvastatin can significantly inhibit the activation of pyroptosis signaling. The exogenous addition of geranylgeranyl pyrophosphate (GGPP),a key metabolite of the mevalonate pathway, can significantly reduce sensitivity to 5-FU,and simvastatin combined with 5-FU demonstrates a strong synergistic effect. Furthermore, in organoid models and genetically engineered mice with spontaneous PC, the combination of simvastatin and 5-FU significantly inhibits tumor growth. In conclusion, our study reveals the critical role of the mevalonate pathway in 5-FU resistance and proposes a clinically feasible combination therapy strategy.","manuscriptTitle":"Targeting Mevalonate Pathway Enhances the efficacy of 5-Fluorouracil by regulating pyroptosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-07 13:43:28","doi":"10.21203/rs.3.rs-5024083/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-23T12:28:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-17T07:02:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"285222025341754359967114828865189503507","date":"2024-10-08T01:52:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54124320410505593730240028704196684234","date":"2024-09-22T03:27:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-07T21:17:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-04T03:58:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-04T03:57:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Medical Oncology","date":"2024-09-03T10:11:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"medical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"medo","sideBox":"Learn more about [Medical Oncology](https://www.springer.com/journal/12032)","snPcode":"12032","submissionUrl":"https://submission.nature.com/new-submission/12032/3","title":"Medical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"749d9624-12f2-49b1-95c6-145196f0a51c","owner":[],"postedDate":"November 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-25T16:03:20+00:00","versionOfRecord":{"articleIdentity":"rs-5024083","link":"https://doi.org/10.1007/s12032-024-02557-5","journal":{"identity":"medical-oncology","isVorOnly":false,"title":"Medical Oncology"},"publishedOn":"2024-11-20 15:57:49","publishedOnDateReadable":"November 20th, 2024"},"versionCreatedAt":"2024-11-05 19:39:15","video":"","vorDoi":"10.1007/s12032-024-02557-5","vorDoiUrl":"https://doi.org/10.1007/s12032-024-02557-5","workflowStages":[]},"version":"v2","identity":"rs-5024083","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5024083","identity":"rs-5024083","version":["v2"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}