Nakayama Yuki, Itoh Shinji, Toshima Takeo, Yugawa Kyohei, Yoshiya Shohei, Iseda Norifumi, Tsutsui Yuriko, Toshida Katsuya, Ishikawa Takuma, Yoshizumi Tomoharu
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Fukuoka, 812-8582, Japan.
Int J Clin Oncol. 2025 Jul 25. doi: 10.1007/s10147-025-02818-x.
Ferroptosis, a form of programmed cell death, is a potential target for cancer therapy. Metazoan SpoT Homolog 1 (MESH1) possesses intracellular NADPH phosphatase activity, which has been linked to ferroptosis. However, the molecular effects on the ferroptosis in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate the relationship between MESH1 expression and the prognosis of patients with HCC, as well as its impact on ferroptosis in HCC cells.
We used resected specimens from patients to assess the relationship between MESH1 expression and prognosis. HCC cell lines were used to evaluate the impact of MESH1 expression on the cell phenotype and ferroptosis through various assays, RNA sequencing, and an animal experiment with xenograft mice model.
We found that high MESH1 expression correlated with good outcomes. Further investigation demonstrated that MESH1 also exhibits NADPH phosphatase activity in HCC, contributing to increased sensitivity to ferroptosis when the ferroptosis inducer was used. Similar results were observed with other ferroptosis inducers, sorafenib and lenvatinib. Notably, RNA sequencing analysis of cells with MESH1 KD revealed a correlation between intracellular iron homeostasis and MESH1 levels. These results suggested that MESH1 also can affect ferroptosis sensitivity through changing intracellular iron levels. Tumors derived from MESH1 KD cells in xenograft mice showed reduced sensitivity to sorafenib and lenvatinib, further supporting the role of MESH1 ferroptosis regulation.
This study suggests that MESH1 influences intracellular redox and iron regulatory pathways, both of which are linked to cellular processes associated with ferroptosis.
铁死亡是一种程序性细胞死亡形式，是癌症治疗的潜在靶点。后生动物斑点同源物1（MESH1）具有细胞内NADPH磷酸酶活性，这与铁死亡有关。然而，其对肝细胞癌（HCC）中铁死亡的分子影响仍不清楚。本研究旨在探讨MESH1表达与HCC患者预后的关系，以及其对HCC细胞中铁死亡的影响。
我们使用患者的切除标本评估MESH1表达与预后的关系。通过各种检测、RNA测序以及异种移植小鼠模型的动物实验，利用HCC细胞系评估MESH1表达对细胞表型和铁死亡的影响。
我们发现高MESH1表达与良好预后相关。进一步研究表明，MESH1在HCC中也表现出NADPH磷酸酶活性，当使用铁死亡诱导剂时，其对铁死亡的敏感性增加。使用其他铁死亡诱导剂索拉非尼和仑伐替尼时也观察到类似结果。值得注意的是，对MESH1基因敲低的细胞进行RNA测序分析发现，细胞内铁稳态与MESH1水平之间存在相关性。这些结果表明，MESH1也可通过改变细胞内铁水平来影响铁死亡敏感性。异种移植小鼠中源自MESH1基因敲低细胞的肿瘤对索拉非尼和仑伐替尼的敏感性降低，进一步支持了MESH1对铁死亡的调节作用。
本研究表明，MESH1影响细胞内氧化还原和铁调节途径，这两者均与铁死亡相关的细胞过程有关。
