Zou Liyi, Zhang Taomin, Yang Cui, Liu Weijing, Fahira Aamir, Yang Dongli, Zheng Biao, Yao Xiaojun, Liu Yi, Huang Zunnan
Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, China.
Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Dongguan, Guangdong, China.
Mol Carcinog. 2025 Mar;64(3):580-596. doi: 10.1002/mc.23874. Epub 2025 Jan 6.
The progression of tumors has been demonstrated to have a strong correlation with ferroptosis. Bis(4-hydroxy-3,5-dimethylphenyl) sulfone (TMBPS) has been shown to effectively inhibit the proliferation of hepatocellular carcinoma (HCC), but its underlying mechanism is not clear. In this study, ferrostatin-1 (Fer-1) was employed to explore whether the death of HCC cells caused by TMBPS is related to ferroptosis. The intracellular lipid peroxides, Fe, malondialdehyde (MDA), GSH/GSSG, mitochondrial morphology, and potential of HCC cells were detected after TMBPS treatment. The target of TMBPS was predicted by the molecular docking approach and verified via quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and cellular heat transfer assay (CETSA). Our results revealed that Fer-1 effectively reversed the cell death induced by TMBPS in HCC cells. Treatment with TMBPS induced typical ferroptosis features, including increased levels of intracellular lipid peroxides, Fe, and MDA, along with a decreased GSSH/GSH ratio and mitochondrial potential. These effects were reversed by overexpressing SLC7A11. These findings suggest that the cell death triggered by TMBPS in HCC cells is linked to ferroptosis, potentially mediated through the inhibition of SLC7A11 expression.
肿瘤的进展已被证明与铁死亡有很强的相关性。双（4-羟基-3,5-二甲基苯基）砜（TMBPS）已被证明能有效抑制肝细胞癌（HCC）的增殖，但其潜在机制尚不清楚。在本研究中，使用铁死亡抑制剂1（Fer-1）来探究TMBPS导致的肝癌细胞死亡是否与铁死亡有关。在TMBPS处理后，检测肝癌细胞内的脂质过氧化物、铁、丙二醛（MDA）、谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）、线粒体形态和电位。通过分子对接方法预测TMBPS的作用靶点，并通过定量实时聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法和细胞热迁移分析（CETSA）进行验证。我们的结果显示，Fer-1有效地逆转了TMBPS诱导的肝癌细胞死亡。TMBPS处理诱导了典型的铁死亡特征，包括细胞内脂质过氧化物、铁和MDA水平升高，同时谷胱甘肽二硫化物/谷胱甘肽（GSSH/GSH）比率和线粒体电位降低。过表达溶质载体家族7成员11（SLC7A11）可逆转这些效应。这些发现表明，TMBPS在肝癌细胞中引发的细胞死亡与铁死亡有关，可能是通过抑制SLC7A11的表达介导的。
