Targeting senescence has emerged as a promising strategy for liver cancer treatment. However, the lack of a safe agent capable of inducing complete senescence and being combined with senolytics poses a limitation. Here, we screened a natural product library and identified tryptanthrin (TRYP) as a potent inducer of cellular senescence in liver cancer cells both in vitro and in vivo. Mechanistically, Glutathione S-transferase P1 (GSTP1), a key regulator for redox homeostasis, was identified as a target protein for TRYP-induced senescence. TRYP directly bound to GSTP1 and inhibited its enzymatic activity, mediating reactive oxygen species (ROS) accumulation, followed by DNA damage response (DDR), consequently contributing to initiating primary senescence. Furthermore, TRYP triggered DNA damage-dependent activation of NF-κB pathway, which evoked senescence-associated secretory phenotype (SASP), thereby leading to senescence reinforcement. Importantly, TRYP exposed the vulnerability of tumor cells and sensitized senescent cells to apoptosis induced by senolytic agent ABT263, a Bcl2 inhibitor. Taken together, our findings reveal that TRYP induces cellular senescence via GSTP1/ROS/DDR/NF-κB/SASP axis, providing a novel potential application in synergizing with senolytic therapy in liver cancer.

中文翻译：

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色钽菊酯靶向 GSTP1 诱导衰老，并增加肝癌细胞中 senolytics 对细胞凋亡的敏感性


靶向衰老已成为肝癌治疗的一种有前途的策略。然而，缺乏能够诱导完全衰老并与 senolytics 联合使用的安全药物构成了局限性。在这里，我们筛选了一个天然产物库，并确定色钽菊酯 （TRYP） 是体外和体内肝癌细胞衰老的有效诱导剂。从机制上讲，谷胱甘肽 S-转移酶 P1 （GSTP1） 是氧化还原稳态的关键调节因子，被确定为 TRYP 诱导衰老的靶蛋白。TRYP 直接与 GSTP1 结合并抑制其酶活性，介导活性氧 （ROS） 积累，然后是 DNA 损伤反应 （DDR），从而有助于启动原发性衰老。此外，TRYP 触发了 NF-κB 通路的 DNA 损伤依赖性激活，从而诱发衰老相关分泌表型 （SASP），从而导致衰老强化。重要的是，TRYP 暴露了肿瘤细胞和致敏衰老细胞对 Bcl2 抑制剂 ABT263 诱导的细胞凋亡的脆弱性。综上所述，我们的研究结果显示，TRYP 通过 GSTP1/ROS/DDR/NF-κB/SASP 轴诱导细胞衰老，为与肝癌 senolytic 疗法协同作用提供了新的潜在应用。