Dietary Fructose Suppresses Hepatocellular Carcinogenesis through Fructose 1-Phosphate-Mediated Inhibition of Mannose Phosphate Isomerase

Dietary Fructose Suppresses Hepatocellular Carcinogenesis through Fructose 1-Phosphate-Mediated Inhibition of Mannose Phosphate Isomerase | 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 Biological Sciences - Article Dietary Fructose Suppresses Hepatocellular Carcinogenesis through Fructose 1-Phosphate-Mediated Inhibition of Mannose Phosphate Isomerase Huiyong Yin, Shanshan Zhong, Yongqiang Wang, Ningning Wang, Huimin Jiang, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6049102/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Fructose consumption increases risks of obesity-related metabolic diseases and some cancers, but remains controversial in hepatocellular carcinoma (HCC) 1 . Animal studies suggest high fructose promotes HCC 2,3 , whereas human studies found an inverse correlation between fructose intake and risk of live cancer 4 . Moreover, fructose metabolism is significantly suppressed in HCC, including loss of fructose-1,6-bisphosphate aldolase B (ALDOB) 5-7 . Here we show that dietary fructose suppresses HCC through fructose 1-phosphate (F1P)-mediated inhibition of mannose phosphate isomerase (MPI). We performed single-cell transcriptomics and identified subsets of cancer cells with fructose catabolic capability in human HCC tissues, termed fructophilic hepatoma cells (fp-HCs, SLC2A2 high KHK high ALDOB low ), featuring relatively high expressions of SLC2A2 and ketohexokinase ( KHK ) but low ALDOB expression. Fructose-derived F1P inhibits HCC by remodeling glucose and mannose metabolism in HCC mouse models with aldob liver-specific knockout mice. Mechanistically, F1P competitively binds to and inhibits MPI, reducing protein N-glycosylation and triggering maladaptive ER stress and dilation, ultimately impairing cell viability. Furthermore, we identified Ebselen as a potent MPI inhibitor through screening FDA-approved drugs and validated the efficacy in mouse models. Together, our study reveals a novel mechanism by which dietary fructose inhibits HCC through metabolic rewiring of glucose and mannose, offering a therapeutic strategy to target cancer metabolic vulnerabilities. Biological sciences/Cancer/Cancer metabolism Biological sciences/Cancer/Gastrointestinal cancer/Liver cancer Full Text Additional Declarations There is NO Competing Interest. The human study was approved by the Ethics Committee of Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China. Supplementary Files ExtendedDatatable16.xlsx Extended Data table 1, Extended Data table 2, Extended Data table 3, Extended Data table 4, Extended Data table 5, Extended Data table 6 Cite Share Download PDF Status: Under Review 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-6049102","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":423387851,"identity":"964e7ae9-93e0-41e9-8050-288ddf38486a","order_by":0,"name":"Huiyong Yin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYBACAwbGBiAlwcAPYQDBAQY2GBO/FskGxsYGIrXAGAdg1hDSYi6R3Cbxsc0iz/j44fbHvG0Mcnw3EtgezsCjxXJGYpvkzDaJYrMziY3NQC3GkjcS2A034HPYjcQ2ad42icRtNxjBWhI3AG2RfECMls0zIFrqideyQQKiJcEApAWvw848bLaccU4icQbQLzPnnJMwnHnmYZskPu8bHE9/eONDWV1if/vxBx/elNnI8x1PPibZg0cLELBIMLJBWEw8wDhlYMAbK2DA/IHhD4TF+IOQ2lEwCkbBKBiRAAAWjlSxDvK5IgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7049-1560","institution":"City University of Hong Kong","correspondingAuthor":true,"prefix":"","firstName":"Huiyong","middleName":"","lastName":"Yin","suffix":""},{"id":423387852,"identity":"37c595b3-1f10-4773-a2fe-16598bac298e","order_by":1,"name":"Shanshan Zhong","email":"","orcid":"","institution":"City University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Shanshan","middleName":"","lastName":"Zhong","suffix":""},{"id":423387853,"identity":"44860ece-321e-40ce-94d4-b37d712545bd","order_by":2,"name":"Yongqiang Wang","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yongqiang","middleName":"","lastName":"Wang","suffix":""},{"id":423387854,"identity":"f9f80a9f-efa2-408d-81cb-be25dfd88550","order_by":3,"name":"Ningning Wang","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ningning","middleName":"","lastName":"Wang","suffix":""},{"id":423387855,"identity":"c8c88583-4361-469a-b54d-44344c0a8bc1","order_by":4,"name":"Huimin Jiang","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Huimin","middleName":"","lastName":"Jiang","suffix":""},{"id":423387856,"identity":"e4e3c227-c89a-412d-aa61-3b446c2e3dd3","order_by":5,"name":"Ningning Liang","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ningning","middleName":"","lastName":"Liang","suffix":""},{"id":423387857,"identity":"0ac68f7b-9687-4511-8ce4-413a8a62fd25","order_by":6,"name":"Lili Zhang","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Lili","middleName":"","lastName":"Zhang","suffix":""},{"id":423387858,"identity":"2f3bb900-a2a3-44ff-b2c2-a5afcd740839","order_by":7,"name":"Chunzhao Yin","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). ShanghaiTech University","correspondingAuthor":false,"prefix":"","firstName":"Chunzhao","middleName":"","lastName":"Yin","suffix":""},{"id":423387859,"identity":"71d28d2a-9ad5-4ea4-98b9-2079f865725a","order_by":8,"name":"Qiaochu Tu","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). ShanghaiTech University","correspondingAuthor":false,"prefix":"","firstName":"Qiaochu","middleName":"","lastName":"Tu","suffix":""},{"id":423387860,"identity":"ee8b44d1-73de-4ea5-be64-912cc4be50c9","order_by":9,"name":"Rui Li","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). ShanghaiTech University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Li","suffix":""},{"id":423387861,"identity":"fba0263f-659b-4f82-bbea-caaac2495009","order_by":10,"name":"Chenxi Du","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). ShanghaiTech University","correspondingAuthor":false,"prefix":"","firstName":"Chenxi","middleName":"","lastName":"Du","suffix":""},{"id":423387862,"identity":"3774d3c0-97a5-4f71-8850-e20c6dfcca92","order_by":11,"name":"Jingwen Lv","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Jingwen","middleName":"","lastName":"Lv","suffix":""},{"id":423387863,"identity":"99e02d20-9deb-4077-a34e-9221ecce6b64","order_by":12,"name":"Haorao Ma","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS). University of Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Haorao","middleName":"","lastName":"Ma","suffix":""},{"id":423387864,"identity":"268ced54-201c-470c-a532-8aa7eb038dfc","order_by":13,"name":"Xin Chen","email":"","orcid":"","institution":"Shanghai Institute of Nutrition and Health","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Chen","suffix":""},{"id":423387865,"identity":"031aa10d-177c-472b-a888-1fe0a534cba2","order_by":14,"name":"Guijun Liu","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Guijun","middleName":"","lastName":"Liu","suffix":""},{"id":423387866,"identity":"c031aede-060e-4c06-a5dd-0dae21844d51","order_by":15,"name":"Xuan Yuan","email":"","orcid":"","institution":"Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Xuan","middleName":"","lastName":"Yuan","suffix":""},{"id":423387867,"identity":"df9c980c-3e23-4177-8cdb-4b5df3c1d130","order_by":16,"name":"Yongzhen Tao","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS).","correspondingAuthor":false,"prefix":"","firstName":"Yongzhen","middleName":"","lastName":"Tao","suffix":""},{"id":423387868,"identity":"8ce3460e-57b6-495f-a59b-7f1fc809fae0","order_by":17,"name":"Xiangyang Zhang","email":"","orcid":"","institution":"Department of Oncology, Xiangya Hospital, Central South University.City University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Xiangyang","middleName":"","lastName":"Zhang","suffix":""},{"id":423387869,"identity":"f9b029e1-fc2d-46e6-8886-2970a9804b33","order_by":18,"name":"Hualing Xu","email":"","orcid":"","institution":"City University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Hualing","middleName":"","lastName":"Xu","suffix":""},{"id":423387870,"identity":"7d8d6397-c060-4303-8cfb-31716d880b4e","order_by":19,"name":"Xinran Kong","email":"","orcid":"","institution":"Renji Hospital, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Xinran","middleName":"","lastName":"Kong","suffix":""},{"id":423387871,"identity":"ea8164cf-8a31-45f3-be9e-36b1c8a30d28","order_by":20,"name":"Jun Qin","email":"","orcid":"","institution":"Renji Hospital, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Qin","suffix":""},{"id":423387872,"identity":"5c2d281d-3e3d-46f2-a349-f035f3aa2c02","order_by":21,"name":"Shengxian Li","email":"","orcid":"","institution":"Department of Physiology \u0026 Biophysics, University of Illinois at Chicago","correspondingAuthor":false,"prefix":"","firstName":"Shengxian","middleName":"","lastName":"Li","suffix":""},{"id":423387873,"identity":"5be3cb21-4415-4604-96af-7511b1962799","order_by":22,"name":"Shan Zeng","email":"","orcid":"https://orcid.org/0000-0002-0988-723X","institution":"Xiangya Hospital, Central South University","correspondingAuthor":false,"prefix":"","firstName":"Shan","middleName":"","lastName":"Zeng","suffix":""},{"id":423387874,"identity":"cc799cbb-2a56-4c41-99f4-a10ee4c3f69c","order_by":23,"name":"Hong Shen","email":"","orcid":"","institution":"Department of Oncology, Xiangya Hospital, Central South University.","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Shen","suffix":""},{"id":423387875,"identity":"e7360553-a884-4f06-bd73-66d6e9f1aa1d","order_by":24,"name":"Shiting Chen","email":"","orcid":"","institution":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS).","correspondingAuthor":false,"prefix":"","firstName":"Shiting","middleName":"","lastName":"Chen","suffix":""},{"id":423387876,"identity":"faaf4274-ce65-4d47-8e1c-aed37972d088","order_by":25,"name":"Marcus Goncalves","email":"","orcid":"","institution":"New York University Grossman School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Marcus","middleName":"","lastName":"Goncalves","suffix":""}],"badges":[],"createdAt":"2025-02-17 15:03:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6049102/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6049102/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80227496,"identity":"dba5f5f7-257c-49df-9767-b680e3ec1800","added_by":"auto","created_at":"2025-04-09 11:54:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10244949,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Wangmanuscript02162025final2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6049102/v1_covered_5a145a28-3d3b-440e-92b2-2f7c9804c2d6.pdf"},{"id":80226495,"identity":"9f273957-1fc6-40b0-817f-f9dbf94e8933","added_by":"auto","created_at":"2025-04-09 11:46:09","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":160784,"visible":true,"origin":"","legend":"Extended Data table 1, Extended Data table 2, Extended Data table 3, Extended Data table 4, Extended Data table 5, Extended Data table 6","description":"","filename":"ExtendedDatatable16.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6049102/v1/3316790036eda6384bc5f94b.xlsx"}],"financialInterests":"\u003cp\u003eThere is \u003cstrong\u003eNO\u003c/strong\u003e Competing Interest.\u003c/p\u003e\n\u003cp\u003eThe human study was approved by the Ethics Committee of Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.\u003c/p\u003e","formattedTitle":"Dietary Fructose Suppresses Hepatocellular Carcinogenesis through Fructose 1-Phosphate-Mediated Inhibition of Mannose Phosphate Isomerase","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6049102/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6049102/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Fructose consumption increases risks of obesity-related metabolic diseases and some cancers, but remains controversial in hepatocellular carcinoma (HCC)\u003csup\u003e1\u003c/sup\u003e. Animal studies suggest high fructose promotes HCC\u003csup\u003e2,3\u003c/sup\u003e, whereas human studies found an inverse correlation between fructose intake and risk of live cancer\u003csup\u003e4\u003c/sup\u003e. Moreover, fructose metabolism is significantly suppressed in HCC, including loss of fructose-1,6-bisphosphate aldolase B (ALDOB)\u003csup\u003e5-7\u003c/sup\u003e. Here we show that dietary fructose suppresses HCC through fructose 1-phosphate (F1P)-mediated inhibition of mannose phosphate isomerase (MPI). We performed single-cell transcriptomics and identified subsets of cancer cells with fructose catabolic capability in human HCC tissues, termed fructophilic hepatoma cells (fp-HCs, \u003ci\u003eSLC2A2\u003c/i\u003e\u003csup\u003ehigh\u003c/sup\u003e\u003ci\u003eKHK\u003c/i\u003e\u003csup\u003ehigh\u003c/sup\u003e\u003ci\u003eALDOB\u003c/i\u003e\u003csup\u003elow\u003c/sup\u003e), featuring relatively high expressions of \u003ci\u003eSLC2A2\u003c/i\u003e and ketohexokinase (\u003ci\u003eKHK\u003c/i\u003e) but low \u003ci\u003eALDOB\u003c/i\u003e expression. \r\nFructose-derived F1P inhibits HCC by remodeling glucose and mannose metabolism in HCC mouse models with aldob liver-specific knockout mice. Mechanistically, F1P competitively binds to and inhibits MPI, reducing protein N-glycosylation and triggering maladaptive ER stress and dilation, ultimately impairing cell viability. Furthermore, we identified Ebselen as a potent MPI inhibitor through screening FDA-approved drugs and validated the efficacy in mouse models. Together, our study reveals a novel mechanism by which dietary fructose inhibits HCC through metabolic rewiring of glucose and mannose, offering a therapeutic strategy to target cancer metabolic vulnerabilities.","manuscriptTitle":"Dietary Fructose Suppresses Hepatocellular Carcinogenesis through Fructose 1-Phosphate-Mediated Inhibition of Mannose Phosphate Isomerase","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-09 11:46:04","doi":"10.21203/rs.3.rs-6049102/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-cancer","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcancer","sideBox":"Learn more about [Nature Cancer](http://www.nature.com/natcancer/)","snPcode":"","submissionUrl":"","title":"Nature Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4ecce54f-e4ee-4229-a6ce-e89919b8b5f4","owner":[],"postedDate":"April 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":45119761,"name":"Biological sciences/Cancer/Cancer metabolism"},{"id":45119762,"name":"Biological sciences/Cancer/Gastrointestinal cancer/Liver cancer"}],"tags":[],"updatedAt":"2025-04-09T11:46:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-09 11:46:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6049102","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6049102","identity":"rs-6049102","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}