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<p>Circadian genes are closely associated with tumor development and its sensitivity to chemotherapeutic agents. In triple-negative breast cancer (TNBC), the core circadian gene BMAL1 exhibits an aberrant expression pattern, but its mechanism of influencing TNBC chemosensitivity remains unknown. In this study, we demonstrate that BMAL1 acts as an oncogene in TNBC. Using BMAL1 siRNA-loaded lipid nanoparticles (LNPs), we effectively silenced BMAL1 expression both in vitro and in vivo, resulting in enhanced apoptosis and reduced proliferation of TNBC cells. Notably, BMAL1 suppression following chemotherapy-induced DNA damage impairs the RPA–ATR–CHK1 DNA repair axis, leading to S-phase arrest and accumulation of unrepaired DNA damage. This synergistically increases the sensitivity of TNBC cells to etoposide. Our findings reveal BMAL1 as a promising therapeutic target and support the potential of silencing BMAL1 with siRNA as a neoadjuvant strategy in combination with chemotherapeutic agents for the treatment of TNBC.</p>

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BMAL1 silencing as a promising chemosensitizing strategy for triple-negative breast cancer

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Lu-yi Wang,
  • Xue-han Xu,
  • Wen-jing Xuan,
  • Xin-yue Bi,
  • Qin Zhou

摘要

Circadian genes are closely associated with tumor development and its sensitivity to chemotherapeutic agents. In triple-negative breast cancer (TNBC), the core circadian gene BMAL1 exhibits an aberrant expression pattern, but its mechanism of influencing TNBC chemosensitivity remains unknown. In this study, we demonstrate that BMAL1 acts as an oncogene in TNBC. Using BMAL1 siRNA-loaded lipid nanoparticles (LNPs), we effectively silenced BMAL1 expression both in vitro and in vivo, resulting in enhanced apoptosis and reduced proliferation of TNBC cells. Notably, BMAL1 suppression following chemotherapy-induced DNA damage impairs the RPA–ATR–CHK1 DNA repair axis, leading to S-phase arrest and accumulation of unrepaired DNA damage. This synergistically increases the sensitivity of TNBC cells to etoposide. Our findings reveal BMAL1 as a promising therapeutic target and support the potential of silencing BMAL1 with siRNA as a neoadjuvant strategy in combination with chemotherapeutic agents for the treatment of TNBC.