{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:57:13Z","timestamp":1793278633754,"version":"4.5.0"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Chromosomal translocations involving nucleoporin (NUP) loci, such as NUP98 and NUP214, are recurrent in acute myeloid leukemia (AML). However, the intrinsic functions of wild-type nucleoporins in AML remain largely unknown. By screening the NUP family, we identified NUP214 as a frequently overexpressed gene and a critical fitness determinant in leukemia stem cells (LSCs). NUP214 acts as a conserved driver of LSC survival by restricting heme catabolism, limiting Fe\u00b2\u207a accumulation, and suppressing lipid peroxidation. Conversely, NUP214 deficiency leads to upregulation of heme oxygenase 1 (HMOX1) and arachidonate 15-lipoxygenase (ALOX15), causing heme exhaustion and excessive lipid peroxidation, which ultimately triggers ferroptosis in LSCs and impairs AML progression. Mechanistically, NUP214 translocates into the nucleoplasm where it blocks Sub1-mediated RNA polymerase II recruitment to repress transcription of the key pro-ferroptotic genes HMOX1 and ALOX15, revealing a non-canonical role beyond its nuclear pore function. Furthermore, we developed the small-molecule compound 0449-b, which acts as a selective NUP214 degrader by recruiting NUP214 to the Cullin5-Rbx2 E3 ligase complex, inducing its neddylation and proteasomal degradation. 0449-b potently triggers LSC ferroptosis and exhibits anti-leukemic activity in vivo, while sparing normal hematopoietic stem cells. Collectively, our findings establish NUP214 as a critical oncoprotein that orchestrates heme metabolism and lipid peroxidation to sustain LSCs, and highlight NUP214-targeted degradation as a promising intervention strategy for AML.<\/jats:p>","DOI":"10.1182\/blood.2026033244","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:06:32Z","timestamp":1787677592000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6411-9065","authenticated-orcid":false,"given":"Zhe","family":"Chen","sequence":"first","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0570-4280","authenticated-orcid":false,"given":"Feng","family":"Wu","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5346-3098","authenticated-orcid":false,"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0724-1951","authenticated-orcid":false,"given":"Qiang","family":"Gong","sequence":"additional","affiliation":[{"name":"Army Medical University, CHONGQING, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-2826","authenticated-orcid":false,"given":"Yue","family":"Wei","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6185-4999","authenticated-orcid":false,"given":"Linfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Guizhou University, Guiyang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueya","family":"Zhao","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, CHONGQING, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Hematology, Children&#x92;s Hospital of Chongqing Medical University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqing","family":"Zeng","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianchuan","family":"Deng","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3573-6803","authenticated-orcid":false,"given":"Hua-bing","family":"Li","sequence":"additional","affiliation":[{"name":"shanghai jiao tong university, shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7692-5067","authenticated-orcid":false,"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zufeng","family":"Guo","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3896-5321","authenticated-orcid":false,"given":"Yu","family":"Hou","sequence":"additional","affiliation":[{"name":"Chongqing Medical University, CHONGQING, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,8,25]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033244\/2541442\/blood.2026033244.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033244\/2541442\/blood.2026033244.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:06:32Z","timestamp":1787677592000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2026033244\/570510\/Inhibition-of-nucleoporin-214-depletes-leukemia"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2026033244","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"article-number":"blood.2026033244"}}