The Caspase-1-EGR4 axis drives acute myeloid leukemia progression by orchestrating macrophage repolarization

The Caspase-1-EGR4 axis drives acute myeloid leukemia progression by orchestrating macrophage repolarization | 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 The Caspase-1-EGR4 axis drives acute myeloid leukemia progression by orchestrating macrophage repolarization Yi Qian, Yue Chen, Zuxi Feng, Xiaofeng Zhu, Li Zhang, Hao Xiong, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8429347/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 14 You are reading this latest preprint version Abstract The polarization of tumor-associated macrophages (TAMs) toward an M2-like phenotype critically promotes acute myeloid leukemia (AML) progression. Building on the clinical observation that Caspase-1 (CASP1) expression is elevated in AML and correlates with M2 macrophage abundance, we identify a novel signaling axis in AML cells, involving CASP1 and the transcription factor early growth response protein 4 (EGR4), that orchestrates macrophage polarization. Knockdown (KD) of CASP1 in human AML cells (THP-1, MOLM-13) shifted their secretome, which consequently skewed macrophage polarization from M2 to M1 at multiple levels. Mechanistically, transcriptomic sequencing revealed that CASP1 KD significantly upregulated EGR4 expression. Crucially, EGR4 interference partially reversed the macrophage-polarizing effects of CASP1 KD, establishing EGR4 as an essential downstream effector. In a xenograft model using NOD/SCID mice—a defined system for studying human AML-macrophage crosstalk—CASP1 KD potently suppressed tumor growth. Immunohistochemical analysis revealed a remodeled microenvironment characterized by reduced proliferation (Ki67), upregulated EGR4, suppression of the M2-associated IL-10/p-STAT3 pathway and CD206, and elevation of the M1 marker CD86. In conclusion, our integrated analysis delineates a novel AML cell-intrinsic pathway wherein CASP1 promotes disease progression via negative regulation of EGR4, promoting an M2-like macrophage phenotype via the IL-10/p-STAT3 pathway. The identification of the CASP1-EGR4 axis, in addition to explaining the mechanistic link between CASP1 and poor prognosis, highlights a promising therapeutic target for reshaping the innate immune landscape in AML. Biological sciences/Cancer Biological sciences/Cell biology Biological sciences/Computational biology and bioinformatics Biological sciences/Immunology Health sciences/Oncology Acute myeloid leukemia CASP1 EGR4 Macrophage polarization Tumor microenvironment Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterialSR1.pdf SupplementaryDatasetOriginalWesternBlotImages.pdf Cite Share Download PDF Status: Published Journal Publication published 27 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 26 Jan, 2026 Reviews received at journal 23 Jan, 2026 Reviews received at journal 22 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviews received at journal 19 Jan, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 07 Jan, 2026 Editor invited by journal 07 Jan, 2026 Submission checks completed at journal 05 Jan, 2026 First submitted to journal 05 Jan, 2026 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-8429347","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571130373,"identity":"0271d372-039b-4ad1-8a15-16bc9431ae2b","order_by":0,"name":"Yi Qian","email":"","orcid":"","institution":"Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Qian","suffix":""},{"id":571130375,"identity":"500f2258-422f-4e2d-92af-190cff7b01b9","order_by":1,"name":"Yue Chen","email":"","orcid":"","institution":"Lanzhou 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repolarization","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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute myeloid leukemia, CASP1, EGR4, Macrophage polarization, Tumor microenvironment","lastPublishedDoi":"10.21203/rs.3.rs-8429347/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8429347/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe polarization of tumor-associated macrophages (TAMs) toward an M2-like phenotype critically promotes acute myeloid leukemia (AML) progression. Building on the clinical observation that Caspase-1 (CASP1) expression is elevated in AML and correlates with M2 macrophage abundance, we identify a novel signaling axis in AML cells, involving CASP1 and the transcription factor early growth response protein 4 (EGR4), that orchestrates macrophage polarization. Knockdown (KD) of CASP1 in human AML cells (THP-1, MOLM-13) shifted their secretome, which consequently skewed macrophage polarization from M2 to M1 at multiple levels. Mechanistically, transcriptomic sequencing revealed that CASP1 KD significantly upregulated EGR4 expression. Crucially, EGR4 interference partially reversed the macrophage-polarizing effects of CASP1 KD, establishing EGR4 as an essential downstream effector. In a xenograft model using NOD/SCID mice\u0026mdash;a defined system for studying human AML-macrophage crosstalk\u0026mdash;CASP1 KD potently suppressed tumor growth. Immunohistochemical analysis revealed a remodeled microenvironment characterized by reduced proliferation (Ki67), upregulated EGR4, suppression of the M2-associated IL-10/p-STAT3 pathway and CD206, and elevation of the M1 marker CD86.\u003c/p\u003e \u003cp\u003eIn conclusion, our integrated analysis delineates a novel AML cell-intrinsic pathway wherein CASP1 promotes disease progression via negative regulation of EGR4, promoting an M2-like macrophage phenotype via the IL-10/p-STAT3 pathway. The identification of the CASP1-EGR4 axis, in addition to explaining the mechanistic link between CASP1 and poor prognosis, highlights a promising therapeutic target for reshaping the innate immune landscape in AML.\u003c/p\u003e","manuscriptTitle":"The Caspase-1-EGR4 axis drives acute myeloid leukemia progression by orchestrating macrophage repolarization","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-08 15:07:22","doi":"10.21203/rs.3.rs-8429347/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-27T03:54:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-23T16:48:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-22T16:38:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226835188774522461011860587383467689299","date":"2026-01-20T16:18:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190661231469141768564866974210323385449","date":"2026-01-20T16:05:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8468328983161281613393107079978720620","date":"2026-01-20T15:42:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-20T00:46:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102418301464894383205935648370288189971","date":"2026-01-07T18:47:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251196271139064680511135069984030910124","date":"2026-01-07T16:41:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T16:33:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-07T16:30:18+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-07T16:26:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-05T15:44:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-01-05T15:34:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"10a9ab8a-9d15-4cea-b78d-147f56ec17e9","owner":[],"postedDate":"January 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":60776381,"name":"Biological sciences/Cancer"},{"id":60776382,"name":"Biological sciences/Cell biology"},{"id":60776383,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":60776384,"name":"Biological sciences/Immunology"},{"id":60776385,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-03-02T16:00:48+00:00","versionOfRecord":{"articleIdentity":"rs-8429347","link":"https://doi.org/10.1038/s41598-026-41381-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-02-27 15:57:41","publishedOnDateReadable":"February 27th, 2026"},"versionCreatedAt":"2026-01-08 15:07:22","video":"","vorDoi":"10.1038/s41598-026-41381-x","vorDoiUrl":"https://doi.org/10.1038/s41598-026-41381-x","workflowStages":[]},"version":"v1","identity":"rs-8429347","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8429347","identity":"rs-8429347","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}