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Bloom syndrome protein (BLM), a RecQ family DNA helicase, is consistently overexpressed in multiple malignancies, yet its therapeutic potential remains largely unexplored. 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 BLM 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-BLM-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&Tag-seq, G4-CUT&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 BLM gene upregulation mediated by BLM-G4-STAT1 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.