Temsirolimus抑制FSP1酶活性以诱导铁死亡并抑制肝癌进展
Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression
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影响因子:5.9
分区:生物学2区 / 细胞生物学3区
发表日期:2025 Jan 30
作者:
Rui-Lin Tian, Tian-Xiang Wang, Zi-Xuan Huang, Zhen Yang, Kun-Liang Guan, Yue Xiong, Pu Wang, Dan Ye
DOI:
10.1093/jmcb/mjae036
摘要
铁死亡是一种非凋亡性的细胞死亡方式，其特征为铁依赖的脂质过氧化物积累。谷胱甘肽过氧化物酶4(GPX4)催化的脂质自由基清除反应是主要的抗铁死亡机制，药理学抑制该途径被认为具有潜在的抗肿瘤作用。然而，某些肿瘤细胞在脂质自由基清除途径中表现出冗余，使其对GPX4抑制剂无反应。本研究通过筛选不同癌细胞系及FDA批准药物，发现temsirolimus联合GPX4抑制剂RSL3能有效诱导肝癌细胞的铁死亡。机制上，temsirolimus通过直接结合并抑制铁死亡抑制蛋白1(FSP1)酶，增强肝癌细胞的铁死亡敏感性。值得注意的是，虽然temsirolimus作为一种强效的哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂，但其诱导铁死亡的作用主要归因于抑制FSP1而非mTOR活性。通过体外细胞克隆形成实验和体内肿瘤异种移植模型，验证了temsirolimus与RSL3的联合能有效抑制肝肿瘤的进展。这一抗肿瘤作用与脂质过氧化的增加和铁死亡的诱导相关。总结而言，我们的研究强调了联合多靶点铁死亡诱导剂以绕过肝癌细胞铁死亡抗性的重要性，并指出temsirolimus作为潜在的FSP1抑制剂和铁死亡诱导剂，值得在转化医学中进一步探索。
Abstract
Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation. While lipid radical elimination reaction catalyzed by glutathione peroxidase 4 (GPX4) is a major anti-ferroptosis mechanism, inhibiting this pathway pharmaceutically shows promise as an antitumor strategy. However, certain tumor cells exhibit redundancy in lipid radical elimination pathways, rendering them unresponsive to GPX4 inhibitors. In this study, we conducted screens across different cancer cell lines and Food and Drug Administration-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. Mechanistically, temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme. Notably, while temsirolimus is recognized as a potent mammalian target of rapamycin (mTOR) inhibitor, its ferroptosis-inducing effect is primarily attributed to the inhibition of FSP1 rather than mTOR activity. By employing in vitro colony formation assays and in vivo tumor xenograft models, we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multitarget ferroptosis-inducing agents to circumvent the resistance to ferroptosis of liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.