针对衰老已成为肝癌治疗的一种有前景的策略。然而，缺乏能够诱导完全衰老并与衰老抑制剂联合使用的安全药物造成了限制。在这里，我们筛选了一个天然产物库，并在体外和体内鉴定出色胺酮（TRYP）是肝癌细胞细胞衰老的有效诱导剂。从机制上讲，氧化还原稳态的关键调节剂谷胱甘肽 S-转移酶 P1 (GSTP1) 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，随后引发 DNA 损伤反应 (DDR)，从而有助于启动初级衰老。此外，TRYP 触发 DNA 损伤依赖性 NF-κB 通路激活，引发衰老相关分泌表型 (SASP)，从而导致衰老强化。重要的是，TRYP 暴露了肿瘤细胞的脆弱性，并使衰老细胞对由 senolytic agent ABT263（一种 Bcl2 抑制剂）诱导的细胞凋亡敏感。总而言之，我们的研究结果表明，TRYP 通过 GSTP1/ROS/DDR/NF-κB/SASP 轴诱导细胞衰老，为肝癌的抗衰老治疗提供了一种新的潜在应用。版权所有 © 2024。由 Elsevier B.V. 出版。

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.Copyright © 2024. Published by Elsevier B.V.