{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T23:38:15Z","timestamp":1775345895714,"version":"3.50.1"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81760033"],"award-info":[{"award-number":["81760033"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160030"],"award-info":[{"award-number":["82160030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:p>\n                    Tyrosine kinase inhibitors (TKIs), targeted therapeutic agents, have significantly improved survival outcomes in patients with chronic myeloid leukemia (CML). However, the emergence of drug resistance remains a challenge, with the underlying mechanisms still largely unknown. Deubiquitinating enzymes (DUBs) have been reported as potential targets in many human cancers. In this study, we identified ubiquitin\u2010specific protease 8 (USP8) as a potential prognostic target for CML drug resistance through bioinformatics analysis and validation in clinical samples. Functionally, knockdown of\n                    <jats:italic>USP8<\/jats:italic>\n                    inhibited proliferation and increased apoptosis and TKI sensitivity in various CML cell lines. Mechanistically, immunoprecipitation\u2010mass spectrometry analysis and molecular docking demonstrated an interaction between USP8 and eukaryotic translation initiation factor 2 subunit alpha (EIF2S1). USP8 stabilizes EIF2S1 protein by inhibiting its K48\u2010linked ubiquitination, thereby preventing its degradation via the proteasome pathway. In other words,\n                    <jats:italic>USP8<\/jats:italic>\n                    knockdown suppressed EIF2S1 protein expression and inhibited tumor growth both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , further suppressing TKI resistance. In summary, our results suggest that\n                    <jats:italic>USP8<\/jats:italic>\n                    is overexpressed in CML and linked to resistance to TKIs. We have unveiled a previously unknown mechanism of CML drug resistance, which may provide novel perspectives on the advancement of targeted therapeutic strategies and clinical interventions.\n                  <\/jats:p>","DOI":"10.1111\/febs.70300","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:10:01Z","timestamp":1761664201000},"page":"1302-1322","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The deubiquitinating enzyme\n                    <scp>USP<\/scp>\n                    8 promotes tyrosine kinase inhibitors resistance in chronic myeloid leukemia by stabilizing\n                    <scp>EIF<\/scp>\n                    2\n                    <scp>S<\/scp>\n                    1 protein"],"prefix":"10.1111","volume":"293","author":[{"given":"Shan","family":"Zhang","sequence":"first","affiliation":[{"name":"The Department of Hematology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hurong","family":"Lai","sequence":"additional","affiliation":[{"name":"The Department of Hematology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanwan","family":"Bao","sequence":"additional","affiliation":[{"name":"The Department of Hematology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caifeng","family":"Liao","sequence":"additional","affiliation":[{"name":"The Department of Hematology The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  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