{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:12:51Z","timestamp":1786119171404,"version":"build-2736575974"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>This study was designed to investigate the effects of zeylonone (Zey) on attenuating tamoxifen (TAM) resistance in breast cancer cells in vitro and in vivo and its underlying mechanisms. Database analysis and clinical sample validation revealed that CENPK is significantly upregulated in breast cancer tissues and TAM\u2010resistant cells, and its expression positively correlates with CTCF mRNA levels. Knockdown of CENPK markedly suppressed proliferation and colony formation, induced G0\/G1 cell cycle arrest, promoted apoptosis in MCF\u20107\/TAM cells, and inhibited tumor growth in nude mice, thereby attenuating TAM resistance. Zey treatment resulted in dose\u2010 and time\u2010dependent downregulation of both CTCF and CENPK at the protein and mRNA levels. Molecular docking provided preliminary computational evidence suggesting Zey can bind to CTCF (binding energy:\u22126.9 kcal\/mol), with subsequent biophysical and functional assays supporting this interaction, and thermal shift assays demonstrated that Zey enhances the thermal stability of CTCF. ChIP\u2010qPCR and luciferase reporter assays confirmed that CTCF directly binds to the CENPK promoter and positively regulates its transcription, and Zey inhibits this regulatory process by directly binding to CTCF. Mechanistically, the CTCF\/CENPK axis is associated with JAK1\/STAT3 pathway modulation (increasing phosphorylation levels of JAK1 and STAT3), and Zey significantly reduces pathway activity by suppressing this axis. Overexpression of CTCF attenuated the anti\u2010resistance effects of Zey, whereas knockdown of CENPK or JAK1 restored Zey's efficacy. While CTCF and CENPK have been individually implicated in cancer progression, this study provides the first evidence linking them in a functional regulatory axis that drives tamoxifen resistance. Zey attenuates tamoxifen resistance in breast cancer cells by directly binding to CTCF, thereby inhibiting CTCF\u2010mediated transcriptional regulation of CENPK, downregulating CENPK expression, and subsequently suppressing the JAK1\/STAT3 signaling pathway.<\/jats:p>","DOI":"10.1002\/ddr.70255","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:21:26Z","timestamp":1773033686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zeylenone Attenuates Tamoxifen Resistance by Directly Binding to CTCF and Inhibiting the CTCF\u2010CENPK\u2010JAK1\/STAT3 Signaling Axis in Breast Cancer"],"prefix":"10.1002","volume":"87","author":[{"given":"Gang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery The Second Affiliated Hospital of Xi'an Medical University Xi'an 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