{"paper_id":"331f24da-6775-4b2c-b5fa-4d889aedf8a9","body_text":"Deuterium Concentration as a Dual Regulator: Depletion Suppresses While Enrichment Amplifies Oncogenic Hallmarks in Lung Adenocarcinoma | 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 Deuterium Concentration as a Dual Regulator: Depletion Suppresses While Enrichment Amplifies Oncogenic Hallmarks in Lung Adenocarcinoma Gabor Csonka, Idikó Somlyai, Gábor Somlyai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8293878/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Deuterium abundance has emerged as a metabolic regulator of oncogenic transcriptional programs, yet its impact on cancer gene networks remains incompletely defined. Methods: We profiled A549 lung adenocarcinoma cells cultured under graded deuterium concentrations (40, 80, 150, 300 ppm) using NanoString nCounter technology. Expression data were subjected to multistep filtering, symbolic trajectory encoding, density‑based spatial clustering (DBSCAN) to identify sentinel outliers, and Gaussian mixture modeling (GMM‑6) to resolve coherent transcriptional modules. Results: DBSCAN analysis identified 11 extreme responder genes that define specific vulnerabilities under deuterium depletion, including suppression of multidrug resistance ( ABCB1 , −42% at 80 ppm), proliferative signaling ( FGFR4 , −19%), and transcriptional amplification ( MYCN , −24%). In contrast, enrichment at 300 ppm drove a global activation of oncogenic pathways (mean +44%), particularly amplifying tumor‑promoting inflammation ( IL6 , TGFBR2 ) and invasion/metastasis ( MMP9 ). GMM‑6 clustering of the remaining core network resolved six functional modules, revealing that depletion selectively disengages the high‑energy programs required for phenotypic plasticity (Cluster 5: TGFB1 , S100A4 ) while leaving basal survival reserves (Cluster 6: BIRC5 , RET ) relatively intact. Conclusions: These findings establish deuterium concentration as a dual regulator of oncogenic transcription. Enrichment fuels a hyper‑proliferative, invasive state, whereas moderate depletion exposes stress‑responsive vulnerabilities by selectively suppressing drug resistance, growth factor signaling, and invasive plasticity in the A549 lung adenocarcinoma model. Deuterium modulation A549 cells NanoString profiling DBSCAN clustering Gaussian Mixture Model Mahalanobis distance outliers drug resistance growth factor signaling transcriptional amplification lung adenocarcinoma Full Text Additional Declarations Competing interest reported. The authors declare that this research was conducted by HYD LLC for Cancer Research and Drug Development. HYD LLC registered Vetera-DDW-25 deuterium-depleted anticancer medicinal product to treat household pets and commercialized Preventa deuterium-depleted drinking waters for human use. Supplementary Files 1204Supportingdata.docx Cite Share Download PDF Status: Posted Version 1 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8293878\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":557207941,\"identity\":\"77ef3fe4-ed95-4d11-8c62-0f3beb62f6f1\",\"order_by\":0,\"name\":\"Gabor 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The authors declare that this research was conducted by HYD LLC for Cancer Research and Drug Development. HYD LLC registered Vetera-DDW-25 deuterium-depleted anticancer medicinal product to treat household pets and commercialized Preventa deuterium-depleted drinking waters for human use.\",\"formattedTitle\":\"Deuterium Concentration as a Dual Regulator: Depletion Suppresses While Enrichment Amplifies Oncogenic Hallmarks in Lung Adenocarcinoma\",\"fulltext\":[],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":false,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":true,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":true,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Deuterium modulation, A549 cells, NanoString profiling, DBSCAN clustering, Gaussian Mixture Model, Mahalanobis distance outliers, drug resistance, growth factor signaling, transcriptional amplification, lung adenocarcinoma\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8293878/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8293878/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e\\u003cbr\\u003e\\nDeuterium abundance has emerged as a metabolic regulator of oncogenic transcriptional programs, yet its impact on cancer gene networks remains incompletely defined.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e\\u003cbr\\u003e\\nWe profiled A549 lung adenocarcinoma cells cultured under graded deuterium concentrations (40, 80, 150, 300 ppm) using NanoString nCounter technology. Expression data were subjected to multistep filtering, symbolic trajectory encoding, density‑based spatial clustering (DBSCAN) to identify sentinel outliers, and Gaussian mixture modeling (GMM‑6) to resolve coherent transcriptional modules.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e\\u003cbr\\u003e\\nDBSCAN analysis identified 11 extreme responder genes that define specific vulnerabilities under deuterium depletion, including suppression of multidrug resistance (\\u003cem\\u003eABCB1\\u003c/em\\u003e, −42% at 80 ppm), proliferative signaling (\\u003cem\\u003eFGFR4\\u003c/em\\u003e, −19%), and transcriptional amplification (\\u003cem\\u003eMYCN\\u003c/em\\u003e, −24%). In contrast, enrichment at 300 ppm drove a global activation of oncogenic pathways (mean +44%), particularly amplifying tumor‑promoting inflammation (\\u003cem\\u003eIL6\\u003c/em\\u003e, \\u003cem\\u003eTGFBR2\\u003c/em\\u003e) and invasion/metastasis (\\u003cem\\u003eMMP9\\u003c/em\\u003e). GMM‑6 clustering of the remaining core network resolved six functional modules, revealing that depletion selectively disengages the high‑energy programs required for phenotypic plasticity (Cluster 5: \\u003cem\\u003eTGFB1\\u003c/em\\u003e, \\u003cem\\u003eS100A4\\u003c/em\\u003e) while leaving basal survival reserves (Cluster 6: \\u003cem\\u003eBIRC5\\u003c/em\\u003e, \\u003cem\\u003eRET\\u003c/em\\u003e) relatively intact.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions:\\u003c/strong\\u003e\\u003cbr\\u003e\\nThese findings establish deuterium concentration as a dual regulator of oncogenic transcription. Enrichment fuels a hyper‑proliferative, invasive state, whereas moderate depletion exposes stress‑responsive vulnerabilities by selectively suppressing drug resistance, growth factor signaling, and invasive plasticity in the A549 lung adenocarcinoma model.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Deuterium Concentration as a Dual Regulator: Depletion Suppresses While Enrichment Amplifies Oncogenic Hallmarks in Lung Adenocarcinoma\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-12-11 05:07:08\",\"doi\":\"10.21203/rs.3.rs-8293878/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"ea6d2ec7-28e0-47ed-8193-cc007e5736b5\",\"owner\":[],\"postedDate\":\"December 11th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-17T16:31:58+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-12-11 05:07:08\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8293878\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8293878\",\"identity\":\"rs-8293878\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}