Temsirolimus抑制FSP1酶活性诱导铁铁作用并抑制肝癌进展
Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression
影响因子:5.90000
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
摘要
铁凋亡是一种非凋亡的细胞死亡模式，其特征是铁依赖性脂质过氧化的积累。尽管谷胱甘肽过氧化物酶4（GPX4）催化的脂质自由基消除反应是一种主要的抗肿瘤作用机制，但抑制该途径在药物方面表现出有望作为抗肿瘤策略的希望。但是，某些肿瘤细胞在脂质自由基消除途径中表现出冗余，使它们对GPX4抑制剂无反应。在这项研究中，我们在不同的癌细胞系和食品药物给药批准的药物上进行了筛查，从而导致Temsirolimus与GPX4抑制剂RSL3结合使用，作为肝癌细胞中甲状腺肿的有效诱导剂。从机械上讲，Temsirolimus通过直接结合并抑制铁毒性抑制蛋白1（FSP1）酶来使肝癌细胞敏化肝癌。值得注意的是，虽然Temsirolimus被认为是雷帕霉素（MTOR）抑制剂的有效哺乳动物靶标，但其促氧诱导效应主要归因于FSP1而不是MTOR活性的抑制。通过采用体外菌落形成测定和体内肿瘤异种移植模型，我们证明了Temsirolimus和RSL3的组合有效地抑制了肝肿瘤进展。这种肿瘤作用与脂质过氧化和肌凋亡的诱导有关。总之，我们的发现强调了将多坐铁纤维毒性诱导剂结合起来的潜力，以避免对肝癌细胞的铁质毒性的抗性，并将Temsirolimus作为一种有希望的FSP1抑制剂和肥大毒作用诱导剂，这也值得进一步研究。
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.