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Herein, we focused on targeting the BLM promoter G-quadruplex (BLM-G4) to inhibit the BLM signaling pathway. We first characterized the parallel BLM-G4 in the BLM promoter region. Subsequently, it is shown for the first time that BLM-G4 recruits phosphorylated signal transducer and activator of transcription 1 (pSTAT1) to activate\u00a0BLM expression. Importantly, two natural alkaloids, berberine (BER) and coptisine (COP), compete with STAT1 for binding to BLM-G4, thereby significantly suppressing BLM expression in colon cancer cells. The BER\/COP\u2212BLM-G4 complex structures were determined using nuclear magnetic resonance experiments, which provide valuable insights for the rational design of next-generation BLM-G4-targeting ligands. Beyond BLM regulation, the conjoint analysis of genome-wide STAT1-CUT&amp;Tag-seq, G4-CUT&amp;Tag-seq, and COP-RNA-seq demonstrated STAT1 as a general G4-binding transcription factor and COP as a pan-genomic G4 stabilizer. Furthermore, BER\/COP exhibited a pronounced synergistic effect with olaparib in inducing colon cancer cell death by disrupting DNA repair pathways and intensifying DNA damage. Collectively, our findings reveal a novel epigenetic mechanism of\u00a0BLM gene upregulation mediated by BLM-G4\u2212STAT1 interaction and suggest that the combination therapy of G4 stabilizers with poly(ADP) ribose polymerase (PARP) inhibitors is a promising strategy for treating complex cancers.<\/jats:p>","DOI":"10.1093\/nar\/gkag383","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T11:30:15Z","timestamp":1776166215000},"source":"Crossref","is-referenced-by-count":2,"title":["A small molecule disrupts G4\u2013STAT1 interaction and synergizes with olaparib to drive cancer cell death"],"prefix":"10.1093","volume":"54","author":[{"given":"Yingying","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Joint International Research Laboratory of Target Discovery and New Drug Innovation (Ministry of Education), and Jiangsu Key Laboratory of Bioactive Natural Product Research, China Pharmaceutical 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Jiangsu 211198 ,","place":["PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3197-9472","authenticated-orcid":false,"given":"Jonathan","family":"Dickerhoff","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University , West Lafayette, IN 47907 ,","place":["America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushuang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Joint International Research Laboratory of Target Discovery and New Drug Innovation (Ministry of Education), and Jiangsu Key Laboratory of Bioactive Natural Product Research, China Pharmaceutical University , Nanjing, Jiangsu 211198 ,","place":["PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Joint International Research Laboratory of Target Discovery and New Drug Innovation (Ministry of Education), and Jiangsu Key Laboratory of Bioactive Natural Product Research, China Pharmaceutical University , Nanjing, Jiangsu 211198 ,","place":["PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlei","family":"Bian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Joint International Research Laboratory of Target Discovery and New Drug Innovation (Ministry of Education), and Jiangsu Key Laboratory of Bioactive Natural Product Research, China Pharmaceutical University , Nanjing, Jiangsu 211198 ,","place":["PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-4776","authenticated-orcid":false,"given":"Kewei","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Hunan University , Changsha, Hunan 410082 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