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<p>Triple-negative breast cancer (TNBC), the most aggressive molecular subtype of breast cancer, currently lacks effective therapeutic targets. While radiotherapy and chemotherapy remain the mainstay of treatment, therapy resistance frequently develops due to apoptosis evasion, leading to treatment failure. In this study, we demonstrate that luteolin, a naturally occurring flavonoid, effectively induces pyroptosis in TNBC cells through suppression of the AKT signaling pathway. Network pharmacology analysis and Western blot validation confirmed AKT pathway inhibition, with AKT agonists significantly reversing luteolin-induced pyroptosis. Mechanistically, luteolin upregulates the expression of GSDMD and NLRP3 while promoting the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), indicating activation of the NLRP3 inflammasome-GSDMD pathway. Our findings highlight luteolin as a promising pyroptosis-inducing agent for TNBC therapy, providing novel insights into targeting the AKT-NLRP3-GSDMD axis to overcome treatment resistance and enhance antitumor immunity.</p>

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Luteolin regulates pyroptosis of triple-negative breast cancer cells through AKT signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月17日

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  • Gu Junwei,
  • Lan Tian,
  • Hu Zujian,
  • Luo Hua

摘要

Triple-negative breast cancer (TNBC), the most aggressive molecular subtype of breast cancer, currently lacks effective therapeutic targets. While radiotherapy and chemotherapy remain the mainstay of treatment, therapy resistance frequently develops due to apoptosis evasion, leading to treatment failure. In this study, we demonstrate that luteolin, a naturally occurring flavonoid, effectively induces pyroptosis in TNBC cells through suppression of the AKT signaling pathway. Network pharmacology analysis and Western blot validation confirmed AKT pathway inhibition, with AKT agonists significantly reversing luteolin-induced pyroptosis. Mechanistically, luteolin upregulates the expression of GSDMD and NLRP3 while promoting the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), indicating activation of the NLRP3 inflammasome-GSDMD pathway. Our findings highlight luteolin as a promising pyroptosis-inducing agent for TNBC therapy, providing novel insights into targeting the AKT-NLRP3-GSDMD axis to overcome treatment resistance and enhance antitumor immunity.