Targeting CREB3L2-mediated lipid metabolism overcomes lenvatinib resistance and attenuates the progression of hepatocellular carcinoma

Targeting CREB3L2-mediated lipid metabolism overcomes lenvatinib resistance and attenuates the progression of hepatocellular carcinoma | 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 Article Targeting CREB3L2-mediated lipid metabolism overcomes lenvatinib resistance and attenuates the progression of hepatocellular carcinoma Ying-Hong Shi, Weiren Liu, shiguang yang, Shaoqing Liu, Jie Li, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6284026/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Nov, 2025 Read the published version in Cell Death & Disease → Version 1 posted 7 You are reading this latest preprint version Abstract When hepatocellular carcinoma（HCC）cells exhibit malignant biological behaviors, lipid metabolic reprogramming also occurs concomitantly, and identifying regulators of metabolic reprogramming can provide new potential targets for therapy. In this study, we investigated the mechanisms by which Cyclic adenosine monophosphate-responsive element binding protein 3-like 2(CREB3L2) influences HCC progression and contributes to lenvatinib resistance through modulation of lipid metabolism. Up-regulated expression of CREB3L2 was observed in numerous HCC cohorts and associated with poor survival prognosis of patients. Furthermore, CREB3L2 could facilitate the proliferation and metastatic capacity of HCC cells both in vitro and in vivo. It was found that CREB3L2 influences the proliferation and metastasis of HCC cells by up-regulating sterol regulatory element binding protein 1 (SREBP1), a vital regulatory factor of lipid synthesis for fatty acid production. Additionally, CREB3L2 enhances SREBP1 protein expression and stability through increased acetylation mediated by histone acetyltransferase-1(HAT1). Importantly, targeting CREB3L2 in combination with lenvatinib significantly reduced lenvatinib resistance, inhibiting the progression of CREB3L2 high-expressing HCC tumors. These findings suggest that the CREB3L2/HAT1/SREBP1 regulatory axis drives lenvatinib resistance and HCC progression by impacting lipid metabolism. Targeting CREB3L2 alongside lenvatinib improves the efficacy of treating HCC. Biological sciences/Cancer/Cancer therapy Biological sciences/Cancer/Tumour biomarkers HCC CREB3L2 lipid metabolism SREBP1 lenvatinib Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations (Not answered) Supplementary Files Originalwesternblots.pdf Original western blots Supplementarymaterial.pdf Supplementary material Cite Share Download PDF Status: Published Journal Publication published 24 Nov, 2025 Read the published version in Cell Death & Disease → Version 1 posted Editorial decision: revise 07 May, 2025 Review # 1 received at journal 02 May, 2025 Reviewer # 1 agreed at journal 16 Apr, 2025 Reviewers invited by journal 31 Mar, 2025 Submission checks completed at journal 24 Mar, 2025 First submitted to journal 22 Mar, 2025 Editor assigned by journal 22 Mar, 2025 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. 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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-6284026","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":436393135,"identity":"1797c3cb-f042-48af-a3f4-919587d6dcea","order_by":0,"name":"Ying-Hong Shi","email":"data:image/png;base64,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","orcid":"","institution":"Zhongshan Hospital,Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Ying-Hong","middleName":"","lastName":"Shi","suffix":""},{"id":436393136,"identity":"edbcc7da-b13f-4c32-bf83-fee393dfdb48","order_by":1,"name":"Weiren Liu","email":"","orcid":"","institution":"Zhongshan Hospital, Fudan 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University","correspondingAuthor":false,"prefix":"","firstName":"Xuhui","middleName":"","lastName":"Zhao","suffix":""},{"id":436393143,"identity":"2f0317ad-820f-4258-ac27-f13d415ac137","order_by":8,"name":"Xiaoling Wu","email":"","orcid":"","institution":"Zhongshan Hospital,Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoling","middleName":"","lastName":"Wu","suffix":""},{"id":436393144,"identity":"f016da03-b40a-494c-9e68-2192fdfa11dd","order_by":9,"name":"Jiafeng Chen","email":"","orcid":"","institution":"Zhongshan Hospital,Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Jiafeng","middleName":"","lastName":"Chen","suffix":""},{"id":436393145,"identity":"f17ddc59-61a0-450a-b85b-9421dd0980f0","order_by":10,"name":"Yichao Bu","email":"","orcid":"https://orcid.org/0009-0002-1283-3547","institution":"Zhongshan Hospital,Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Yichao","middleName":"","lastName":"Bu","suffix":""},{"id":436393146,"identity":"2dd8e19d-eb49-41b9-b545-3630cd0a5399","order_by":11,"name":"Shengwei Mao","email":"","orcid":"","institution":"Zhongshan Hospital，Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Shengwei","middleName":"","lastName":"Mao","suffix":""}],"badges":[],"createdAt":"2025-03-22 13:55:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6284026/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6284026/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41419-025-08250-3","type":"published","date":"2025-11-24T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81030849,"identity":"6c89301b-80e0-4bfe-90fe-0d5bca134994","added_by":"auto","created_at":"2025-04-21 11:20:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1002195,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCREB3L2 is upregulated and associates with poor outcomes in HCC.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eRelative expression profiles of CREB3L2 across multiple tumor types with liver\u003c/p\u003e\n\u003cp\u003ehepatocellular carcinoma (LIHC), cholangiocarcinoma (CHOL), lung\u003c/p\u003e\n\u003cp\u003eadenocarcinomastomach(LUAD), colon adenocarcinoma (COAD), rectum \u003cbr\u003e\nadenocarcinoma(READ), and glioblastoma multiformebased(GBM) on the TCGA database.\u003cstrong\u003e(B) \u003c/strong\u003eThe expression profiles of CREB3L2 within three patient specific datasets of HCC sourced from the GEO database (sample identifiers GSE102079, GSE14520, and GSE22405). (\u003cstrong\u003eC\u003c/strong\u003e). Survival prognosis curves of HCC patients with different CREB3L2 expression levels. (\u003cstrong\u003eD\u003c/strong\u003e) The relative expression levels of CREB3L2 mRNA within 30 pairs of HCC tissues and their adjacent non-neoplastic counterparts. (\u003cstrong\u003eE\u003c/strong\u003e) The expression profile of CREB3L2 protein in 10 pairs of liver cancer tissues and their paired adjacent tissues.(\u003cstrong\u003eF\u003c/strong\u003e) Typical immunohistochemical staining images illustrate the distinctions in CREB3L2 expression levels between hepatocellular carcinoma (HCC) tissues and their peritumoral counterparts.(\u003cstrong\u003eG\u003c/strong\u003e) IHC staining scores for the expression of CREB3L2 protein in 176 sets of paired tumor tissues.\u003cstrong\u003e(H-I) \u003c/strong\u003ePrognostic curves showing OS and RFS of patients in Cohort 2(\u003cstrong\u003eJ\u003c/strong\u003e)Multivariate Cox analysis of OS clinical prognostic parameters. *,\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05; **, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01; ***, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/f8bea6bd09321432628c329f.jpg"},{"id":81032058,"identity":"57c82916-d65b-4089-89e1-603c9e4278c3","added_by":"auto","created_at":"2025-04-21 11:28:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1129165,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCREB3L2 facilitates HCC cell proliferation and metastasis in vitro\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA-B\u003c/strong\u003e)The expression patterns of CREB3L2 at the mRNA and protein levels in hepatocellular carcinoma cell lines and normal hepatocyte cell lines. (\u003cstrong\u003eC-D\u003c/strong\u003e)The transfection efficiency of knockdown and overexpression of CREB3L2 in 97H and Huh7 cells.\u003cstrong\u003e(E-G) \u003c/strong\u003eColony formation\u003c/p\u003e\n\u003cp\u003eand EDU assays were implemented following knockdown or overexpression of CREB3L2 in 97H and Huh7 cells.\u003cstrong\u003e(H-J) \u003c/strong\u003eAfter knockdown or overexpression of CREB3L2, scratch wound healing and transwell assays were used to assess the migration and invasion abilities of HCC cells. *,\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05; **, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01; ***, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/629a5252c769da168a0c2be3.jpg"},{"id":81032060,"identity":"3ab4e6be-8309-487f-aa30-ad3cd3cec45d","added_by":"auto","created_at":"2025-04-21 11:28:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":873918,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCREB3L2 facilitates HCC cell proliferation and metastasis in vivo\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A-B) \u003c/strong\u003eSubcutaneous tumor volume and weight changes were evaluated in mice after manipulating CREB3L2 expression (knockdown or overexpression).\u003cstrong\u003e(C-D) \u003c/strong\u003eThe effects of CREB3L2 knockdown or overexpression on nude mice model of pulmonary metastasis. *,P \u0026lt; 0.05; **, P \u0026lt; 0.01; ***, P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/bc1f57483f28972ab555c705.jpg"},{"id":81030861,"identity":"43bdda37-b527-49c0-8a3e-c36398ad7197","added_by":"auto","created_at":"2025-04-21 11:20:18","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1049002,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCREB3L2 modulates fatty acid metabolism pathways.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eVolcano plot showing differentially expressed genes in 97H cells comparing shNC and shCREB3L2 groups.\u003cstrong\u003e(B-C) \u003c/strong\u003eDifferentially expressed genes were conducted to KEGG pathway analysis and GSEA enrichment analysis.\u003cstrong\u003e(D) \u003c/strong\u003eModulation of oleic acid levels in 97H and Huh7 cells upon CREB3L2 knockdown or overexpression.\u003cstrong\u003e(E-F) \u003c/strong\u003eDetermine the levels of triglycerides and cholesterol in 97H and Huh7 cells.\u003cstrong\u003e(G) \u003c/strong\u003eCorrelation analysis reveals the relationship between CREB3L2 and the expression of lipid metabolism regulatory molecules.\u003cstrong\u003e(H) \u003c/strong\u003eCorrelation analysis of CREB3L2 expression with the expression of FASN, ACC1, ACLY, and SCD1 in the TCGA database. \u003cstrong\u003e(I-J)\u003c/strong\u003eAfter knocking down or overexpressing CREB3L2, assess the alteration of FASN, ACC1, ACLY, and SCD1. *,P \u0026lt; 0.05; **, P \u0026lt; 0.01; ***, P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure4.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/05f9f7cdc9e0ab701b74229d.jpg"},{"id":81032063,"identity":"3b38fe48-4adf-4d2f-8fed-c6dc93a912ad","added_by":"auto","created_at":"2025-04-21 11:28:18","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":863668,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCREB3L2 attenuates ubiquitinated degradation of SREBP1 protein by enhancing HAT1-mediated acetylation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eMass spectrometry analysis of a peptide derived from Flag-CREB3L2 immunoprecipitates to show the potential interaction between SREBP1 and CREB3L2.\u003cstrong\u003e(B-C) \u003c/strong\u003eCo-IP and the immunofluorescence confocal microscopy demonstrated the colocalization of CREB3L2 and SREBP1 in Huh7 cells. (\u003cstrong\u003eD\u003c/strong\u003e)The effect of CREB3L2 on SREBP1 protein levels in HCC cells.\u003cstrong\u003e(E) \u003c/strong\u003eWestern blot analysis of the effect of CREB3L2 on the half-life of SREBP1 in HCC cells treated with cycloheximide (CHX) for specified time periods.\u003cstrong\u003e(F) \u003c/strong\u003eThe protein expression level of SREBP1 in 97H-shCREB3L2 cells in the presence of MG132.\u003cstrong\u003e(G) \u003c/strong\u003eThe effect of knockdown or overexpression of CREB3L2 on the ubiquitination level of SREBP1 in HCC cells.\u003cstrong\u003e(H) \u003c/strong\u003eThe effect of CREB3L2 expression levels on the acetylation levels of SREBP1 in HCC cells. (\u003cstrong\u003eI\u003c/strong\u003e) Observation of changes in SREBP1 acetylation levels after transfection with plasmids containing site-directed mutations.(\u003cstrong\u003eJ\u003c/strong\u003e)Mass spectrometry analysis of the acetyltransferase HAT1 potentially interacting with SREBP1.\u003cstrong\u003e(K) \u003c/strong\u003eThe effect of downregulating HAT1 or transfecting acetylation site mutation plasmids on the acetylation levels of SREBP1.\u003cstrong\u003e(L) \u003c/strong\u003eThe effect of knockdown or overexpression of CREB3L2 on the protein expression level of HAT1. \u003cstrong\u003e(M) \u003c/strong\u003eDetection of SREBP1 ubiquitination in Huh7 cells after co-transfection with His-Ub, HA-CREB3L2, Myc-SREBP1 WT, Myc-SREBP1-K395R and Myc-SREBP1-K395Q and treatment with MG132. *,P \u0026lt; 0.05; **, P \u0026lt; 0.01; ***, P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure5.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/2474ece5219bc48d3fe4a22f.jpg"},{"id":81030860,"identity":"735d56ff-be8b-4414-ae9d-d603d20180f2","added_by":"auto","created_at":"2025-04-21 11:20:18","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1168516,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSREBP1 is a functionally important target gene for CREB3L2-mediated\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ebiological behavior in HCC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A-B) \u003c/strong\u003eCCK-8 and EdU proliferation assays conducted in Huh7 cells with CREB3L2 overexpression or SREBP1 knockdown.\u003cstrong\u003e(C) \u003c/strong\u003eWound healing assays conducted after CREB3L2 overexpression or SREBP1 knockdown.\u003cstrong\u003e(D-E) \u003c/strong\u003eAssess the changes in mRNA and protein expression levels of FASN, ACC1, ACLY, and SCD1 in Huh7 cells.\u003cstrong\u003e(F) \u003c/strong\u003eAlterations in triglyceride and cholesterol content in response to CREB3L2 overexpression or SREBP1 knockdown.\u003cstrong\u003e(G-H) \u003c/strong\u003eXenograft tumor growth was assessed following CREB3L2 overexpression or SREBP1 knockdown.\u003cstrong\u003e(I) \u003c/strong\u003eMeasurement of triglyceride levels in harvested xenograft tumors.\u003cstrong\u003e(J) \u003c/strong\u003eIHC analysis of CREB3L2, SREBP1, FASN, ACLY, ACC1, and SCD1 in various tumor subgroups. *,P \u0026lt; 0.05; **, P \u0026lt; 0.01; ***, P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure6.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/bcd0501f42938a03f5dcec22.jpg"},{"id":81032062,"identity":"87d68e03-21fc-49b4-b1f7-4f4bd16dce73","added_by":"auto","created_at":"2025-04-21 11:28:18","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1069029,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTargeting CREB3L2 reverses lenvatinib resistance in HCC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A-B) \u003c/strong\u003eSilencing CREB3L2 in 97H cells significantly increases sensitivity to lenvatinib.\u003cstrong\u003e(C) \u003c/strong\u003eDetermination of cell viability in 97H cells treated with lenvatinib using the CCK-8 assay.\u003cstrong\u003e(D) \u003c/strong\u003eSuppression of CREB3L2 expression markedly enhances lenvatinib-mediated inhibition of tumor cell malignant phenotypes.\u003cstrong\u003e(E) \u003c/strong\u003eKnockdown of CREB3L2 enhances the inhibitory effect of lenvatinib on SREBP1 expression.\u003cstrong\u003e(F-G) \u003c/strong\u003eXenograft tumor growth of 97H cells with CREB3L2 knockdown treated with lenvatinib.\u003cstrong\u003e(H) \u003c/strong\u003eRepresentative lung metastasis sections from different treatment groups of nude mice.\u003cstrong\u003e(I) \u003c/strong\u003eA simple mechanistic diagram for the entire text. *,P \u0026lt; 0.05; **, P \u0026lt; 0.01; ***, P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"figure7.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/db116b9e2b4e7daaf9cd8193.jpg"},{"id":96699793,"identity":"b294a044-4b4d-46c1-a273-769f3c11c106","added_by":"auto","created_at":"2025-11-25 08:17:04","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7910116,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Manuscriptfile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1_covered_22e5b1b9-59c5-44a7-8dbe-a99a808467e1.pdf"},{"id":81030850,"identity":"6dd1ca48-c69b-4117-a47d-7b48a0c69411","added_by":"auto","created_at":"2025-04-21 11:20:18","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":864131,"visible":true,"origin":"","legend":"Original western blots","description":"","filename":"Originalwesternblots.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/f609c2274b7b0896baea6756.pdf"},{"id":81032059,"identity":"c1580927-dcee-4292-a1bf-1e195f6abb4a","added_by":"auto","created_at":"2025-04-21 11:28:18","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":720585,"visible":true,"origin":"","legend":"Supplementary material","description":"","filename":"Supplementarymaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6284026/v1/953fd37c8bd8ac7cf29db3b4.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"Targeting CREB3L2-mediated lipid metabolism overcomes lenvatinib resistance and attenuates the progression of hepatocellular carcinoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cell-death-and-disease","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cddis","sideBox":"Learn more about [Cell Death \u0026 Disease](http://www.nature.com/cddis/)","snPcode":"41419","submissionUrl":"https://mts-cddis.nature.com/cgi-bin/main.plex","title":"Cell Death \u0026 Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HCC, CREB3L2, lipid metabolism, SREBP1, lenvatinib","lastPublishedDoi":"10.21203/rs.3.rs-6284026/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6284026/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhen hepatocellular carcinoma（HCC）cells exhibit malignant biological behaviors, lipid metabolic reprogramming also occurs concomitantly, and identifying regulators of metabolic reprogramming can provide new potential targets for therapy. In this study, we investigated the mechanisms by which Cyclic adenosine monophosphate-responsive element binding protein 3-like 2(CREB3L2) influences HCC progression and contributes to lenvatinib resistance through modulation of lipid metabolism. Up-regulated expression of CREB3L2 was observed in numerous HCC cohorts and associated with poor survival prognosis of patients. Furthermore, CREB3L2 could facilitate the proliferation and metastatic capacity of HCC cells both in vitro and in vivo. It was found that CREB3L2 influences the proliferation and metastasis of HCC cells by up-regulating sterol regulatory element binding protein 1 (SREBP1), a vital regulatory factor of lipid synthesis for fatty acid production. Additionally, CREB3L2 enhances SREBP1 protein expression and stability through increased acetylation mediated by histone acetyltransferase-1(HAT1). Importantly, targeting CREB3L2 in combination with lenvatinib significantly reduced lenvatinib resistance, inhibiting the progression of CREB3L2 high-expressing HCC tumors. These findings suggest that the CREB3L2/HAT1/SREBP1 regulatory axis drives lenvatinib resistance and HCC progression by impacting lipid metabolism. Targeting CREB3L2 alongside lenvatinib improves the efficacy of treating HCC.\u003c/p\u003e","manuscriptTitle":"Targeting CREB3L2-mediated lipid metabolism overcomes lenvatinib resistance and attenuates the progression of hepatocellular carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 11:20:13","doi":"10.21203/rs.3.rs-6284026/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-05-07T14:36:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-05-02T15:36:29+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-04-16T12:15:13+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-03-31T14:19:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T14:16:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cell Death \u0026 Disease","date":"2025-03-22T13:52:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-22T13:52:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cell-death-and-disease","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cddis","sideBox":"Learn more about [Cell Death \u0026 Disease](http://www.nature.com/cddis/)","snPcode":"41419","submissionUrl":"https://mts-cddis.nature.com/cgi-bin/main.plex","title":"Cell Death \u0026 Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8bde4c37-49c0-44d3-a5f1-97589586f24a","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46464137,"name":"Biological sciences/Cancer/Cancer therapy"},{"id":46464138,"name":"Biological sciences/Cancer/Tumour biomarkers"}],"tags":[],"updatedAt":"2025-11-25T08:16:55+00:00","versionOfRecord":{"articleIdentity":"rs-6284026","link":"https://doi.org/10.1038/s41419-025-08250-3","journal":{"identity":"cell-death-and-disease","isVorOnly":false,"title":"Cell Death \u0026 Disease"},"publishedOn":"2025-11-24 05:00:00","publishedOnDateReadable":"November 24th, 2025"},"versionCreatedAt":"2025-04-21 11:20:13","video":"","vorDoi":"10.1038/s41419-025-08250-3","vorDoiUrl":"https://doi.org/10.1038/s41419-025-08250-3","workflowStages":[]},"version":"v1","identity":"rs-6284026","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6284026","identity":"rs-6284026","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}