{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T09:07:20Z","timestamp":1791623240807,"version":"4.3.4"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["iMeta"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Homoharringtonine (HHT) is widely used in combination regimens for acute myeloid leukemia (AML), yet its direct cellular targets remain undefined, limiting precision application. Here, we identified EWS RNA\u2010binding protein 1 (EWSR1) as the primary target of HHT through chemical proteomics and biophysical validation. HHT bound the RNA recognition motif of EWSR1 with micromolar affinity, inducing an allosteric conformational switch that promoted oligomerization and liquid\u2013liquid phase separation (LLPS). EWSR1 condensates selectively recruited the N\n                    <jats:sup>6<\/jats:sup>\n                    \u2010methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) reader YTHDF2, forming cytoplasmic hubs where HHT disrupted YTHDF2\u2013mRNA interactions. This sequestration attenuated m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010mediated RNA decay, stabilizing key transcripts such as\n                    <jats:italic>TNFRSF1B<\/jats:italic>\n                    and\n                    <jats:italic>HMOX1<\/jats:italic>\n                    , and thereby impairing AML cell proliferation. Integrated transcriptomics and single\u2010cell RNA\u2010seq analyses revealed that\n                    <jats:italic>EWSR1<\/jats:italic>\n                    was markedly upregulated in AML, particularly in hematopoietic progenitor and myeloid subpopulations, and high\n                    <jats:italic>EWSR1<\/jats:italic>\n                    expression correlated with poor prognosis and enhanced HHT sensitivity. In vivo, the anti\u2010leukemic efficacy of HHT was significantly diminished upon EWSR1 knockdown, demonstrating that EWSR1 was required for therapeutic response. Collectively, these findings uncover a phase separation\u2010centric mechanism by which HHT exerts anti\u2010AML activity, establish the EWSR1\u2013YTHDF2\u2013m\n                    <jats:sup>6<\/jats:sup>\n                    A\n                    <jats:italic>axis<\/jats:italic>\n                    as a critical regulator of leukemia progression, and position EWSR1 as both a functional target and a predictive biomarker for optimizing HHT\u2010based therapies.\n                  <\/jats:p>","DOI":"10.1002\/imt2.70089","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:01:49Z","timestamp":1761894109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Homoharringtonine suppresses acute myeloid leukemia progression by orchestrating EWSR1 phase separation in an m\n                    <sup>6<\/sup>\n                    A\u2010YTHDF2\u2010dependent mechanism"],"prefix":"10.1002","volume":"4","author":[{"given":"Ting\u2010Ting","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"},{"name":"Institutes of Biomedical Sciences, School of Life Sciences Inner Mongolia University Hohhot China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Yunnan Baiyao International Medical Research Center, International Cancer Institute and State Key Laboratory of Molecular Oncology, MOE Frontiers Science Center for Cancer Integrative Omics, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu\u2010Ying","family":"Pei","sequence":"additional","affiliation":[{"name":"Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Cell and Gene Therapy for Hematologic Malignancies, Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao\u2010Nan","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Pharmacy Inner Mongolia Medical University Hohhot China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang\u2010Fang","family":"Zhuo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze\u2010Kun","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"},{"name":"Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center of Basic Medical Research, Institute of Medical Innovation and Research Peking University Third Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing\u2010Kang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u2010Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Cao","sequence":"additional","affiliation":[{"name":"Yunnan Baiyao International Medical Research Center, International Cancer Institute and State Key Laboratory of Molecular Oncology, MOE Frontiers Science Center for Cancer Integrative Omics, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian\u2010Tian","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University Beijing 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