{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T05:40:07Z","timestamp":1751953207550,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (chromosome 22). This cytogenetic abnormality gives rise to the <jats:italic>BCR::ABL1<\/jats:italic> fusion gene, which encodes the constitutively active BCR-ABL1 protein tyrosine kinase, driving uncontrolled proliferation and impaired apoptosis of hematopoietic stem and progenitor cells, leading to leukemogenesis. Imatinib mesylate (IM), a first-generation tyrosine kinase inhibitor (TKI) specifically targeting the BCR-ABL1 oncoprotein, represents the standard first-line therapy for patients with CML. However, imatinib resistance remains a major therapeutic challenge.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to elucidate the role of the <jats:italic>ZFAS1\/STAT3<\/jats:italic> signaling axis in mediating imatinib resistance in CML by promoting metabolic reprogramming, with a particular focus on alterations in glucose metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Imatinib-resistant (IM-R) K562 cells were used to investigate the functional role of <jats:italic>ZFAS1<\/jats:italic>gene. Following <jats:italic>ZFAS1<\/jats:italic> knockdown, assessments of cell viability, apoptosis, and glucose metabolism were performed. The interaction between ZFAS1 and IGF2BP2, as well as its regulatory effect on <jats:italic>STAT3<\/jats:italic> expression and glycolysis-related genes (including <jats:italic>HIF1\u03b1<\/jats:italic>, <jats:italic>LDHA<\/jats:italic>, and <jats:italic>PDK1<\/jats:italic>) were examined using qRT-PCR and western blotting. Additionally, the impact of STAT3 overexpression and glycolysis inhibition (2-DG) on IM sensitivity were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our findings revealed that <jats:italic>ZFAS1<\/jats:italic> expression was significantly upregulated in IM-R CML patient samples and IM-R K562 cells. Silencing of <jats:italic>ZFAS1<\/jats:italic> enhanced cellular sensitivity to IM, inhibited glucose metabolism reprogramming, and promoted apoptosis. Mechanistically, <jats:italic>ZFAS1<\/jats:italic> was found to interact with IGF2BP2, facilitating the stabilization of <jats:italic>STAT3<\/jats:italic> mRNA and leading to increased <jats:italic>STAT3<\/jats:italic> expression. This, in turn, resulted in the upregulation of key glycolytic genes. Overexpression of <jats:italic>STAT3<\/jats:italic> reversed the effects of <jats:italic>ZFAS1<\/jats:italic> knockdown by restoring glycolytic activity and re-establishing IM resistance. Additionally, 2-DG treatment effectively reversed STAT3-induced IM resistance by inhibiting glycolysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings demonstrate that the ZFAS1\/STAT3 signaling axis contributes to imatinib resistance in CML through the modulation of glucose metabolism. Targeting this regulatory pathway may represent a novel therapeutic strategy to overcome TKI resistance in CML.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1603060","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T05:27:44Z","timestamp":1751952464000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ZFAS1\/STAT3 axis modulates imatinib resistance of chronic myeloid leukemia cells through glucose metabolism 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