Targeting the HERV-K102 Envelope Elicits Pyroptosis and Represents a Novel Therapeutic Strategy for Acute Myeloid Leukemia

Targeting the HERV-K102 Envelope Elicits Pyroptosis and Represents a Novel Therapeutic Strategy for Acute Myeloid Leukemia | 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 the HERV-K102 Envelope Elicits Pyroptosis and Represents a Novel Therapeutic Strategy for Acute Myeloid Leukemia Lihong Zong, Qian Luo, Jingru Zhao, Huyi Lei, Mengyuan Li, Yiyuan Chen, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7976215/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective Human endogenous retroviruses (HERVs) have been the focus of numerous recent studies. HERVs entered the human genome millions of years ago and are associated with various diseases, including cancer and immune regulation. Among them, the HERV-K family exhibits the highest transcriptional activity. However, little is known about the expression of HERVs in acute myeloid leukemia (AML) or their potential as biomarkers and therapeutic targets. This study primarily investigated the role of HERV-K102 in the development of AML and explored its underlying mechanisms. Methods The expression profiles of HERV K102 in AML and normal samples were analyzed using The Cancer Genome Atlas (TCGA) database and AML cell lines. Knockout models were generated through CRISPR-Cas9-mediated deletion of the HERV-K102 envelope (K-ENV). Cell viability and pyroptosis rates were measured using the CCK-8 assay and flow cytometry, respectively. Transcriptome analysis was performed to identify differentially expressed genes and related pathways. Western blotting and detection of pyroptosis markers were conducted. Furthermore, the role of HERV-K102 in AML was validated in an inducible knockout xenograft tumor model. Results HERV-K102 was aberrantly activated and highly expressed in AML, and its expression correlated with poor prognosis. K-ENV depletion inhibited AML cell proliferation and promoted apoptosis. Moreover, K-ENV knockout induced pyroptosis, as indicated by increased lactate dehydrogenase (LDH) release, enhanced cleavage of caspase-1 and gasdermin D (GSDMD), and characteristic morphological features of pyroptotic cells. Mechanistically, transcriptomic and functional analyses demonstrated that this process was mediated by S100A9 upregulation and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. Conclusions Our findings suggest that HERV-K102 ENV plays a critical role in AML pathogenesis and may represent a novel diagnostic and therapeutic target. Full Text Additional Declarations No competing interests reported. Supplementary Files Originaldata.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 17 Jan, 2026 Reviews received at journal 17 Jan, 2026 Reviewers agreed at journal 08 Jan, 2026 Reviews received at journal 25 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers invited by journal 12 Nov, 2025 Editor assigned by journal 12 Nov, 2025 Submission checks completed at journal 12 Nov, 2025 First submitted to journal 29 Oct, 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. 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-7976215","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549290441,"identity":"e3acbb1e-82f1-4339-98b7-616eddaf376a","order_by":0,"name":"Lihong Zong","email":"","orcid":"","institution":"Second Affiliated Hospital of Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Lihong","middleName":"","lastName":"Zong","suffix":""},{"id":549290442,"identity":"386a081b-53a7-4670-af61-54a3d0a618d3","order_by":1,"name":"Qian Luo","email":"","orcid":"","institution":"Second Affiliated Hospital of Zhejiang 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Leukemia","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":false,"email":"","identity":"blood-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"BLOOD RESEARCH","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"VoR Journals","inReviewEnabled":false,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7976215/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7976215/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eHuman endogenous retroviruses (HERVs) have been the focus of numerous recent studies. HERVs entered the human genome millions of years ago and are associated with various diseases, including cancer and immune regulation. Among them, the HERV-K family exhibits the highest transcriptional activity. However, little is known about the expression of HERVs in acute myeloid leukemia (AML) or their potential as biomarkers and therapeutic targets. This study primarily investigated the role of HERV-K102 in the development of AML and explored its underlying mechanisms.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe expression profiles of HERV K102 in AML and normal samples were analyzed using The Cancer Genome Atlas (TCGA) database and AML cell lines. Knockout models were generated through CRISPR-Cas9-mediated deletion of the HERV-K102 envelope (K-ENV). Cell viability and pyroptosis rates were measured using the CCK-8 assay and flow cytometry, respectively. Transcriptome analysis was performed to identify differentially expressed genes and related pathways. Western blotting and detection of pyroptosis markers were conducted. Furthermore, the role of HERV-K102 in AML was validated in an inducible knockout xenograft tumor model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eHERV-K102 was aberrantly activated and highly expressed in AML, and its expression correlated with poor prognosis. K-ENV depletion inhibited AML cell proliferation and promoted apoptosis. Moreover, K-ENV knockout induced pyroptosis, as indicated by increased lactate dehydrogenase (LDH) release, enhanced cleavage of caspase-1 and gasdermin D (GSDMD), and characteristic morphological features of pyroptotic cells. Mechanistically, transcriptomic and functional analyses demonstrated that this process was mediated by S100A9 upregulation and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOur findings suggest that HERV-K102 ENV plays a critical role in AML pathogenesis and may represent a novel diagnostic and therapeutic target.\u003c/p\u003e","manuscriptTitle":"Targeting the HERV-K102 Envelope Elicits Pyroptosis and Represents a Novel Therapeutic Strategy for Acute Myeloid Leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 16:45:12","doi":"10.21203/rs.3.rs-7976215/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-18T03:50:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-17T16:43:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321339300624910298017364317494289341202","date":"2026-01-08T20:27:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-25T19:04:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12990470038234319303081177723096516669","date":"2025-11-15T10:03:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-13T02:09:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-12T14:01:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-12T13:53:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BLOOD RESEARCH","date":"2025-10-29T06:13:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":false,"email":"","identity":"blood-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"BLOOD RESEARCH","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"VoR Journals","inReviewEnabled":false,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fc2cdaaf-c090-4168-9b20-0b53f646770e","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-25T07:38:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 16:45:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7976215","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7976215","identity":"rs-7976215","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}