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Through transcriptomic profiling, circBPTF was found to be markedly overexpressed in chemoresistant samples. Further functional experiments demonstrated that BPTF-665aa, the protein product of circBPTF, plays a pivotal role in mediating resistance. Notably, BPTF-665aa prevents the ubiquitination degradation of full-length BPTF, and promotes chromatin accessibility at key promoter sites, such as that of\n                    <jats:italic>c-Myc<\/jats:italic>\n                    promter 2 (P2), facilitating transcriptional activation crucial for cellular survival and proliferation under therapeutic stress. Structural studies confirmed the motifs of BPTF-665aa, including the Plant Homeodomain (PHD) finger and Bromodomain, essential for its chromatin remodeling function. HY-B0509 was identified as a small-molecule inhibitor of BPTF-665aa, with molecular docking and dynamics simulations showing stable binding to critical residues within the protein\u2019s active site. 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