Yu Lin-Sheng, Liu Jia-Jun, Yang Ming-Hung, Lin Yu-Chun, Chen Chi-Shuo
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
Institute of Medical Device and Imaging, School of Medicine, National Taiwan University, Taipei 106319, Taiwan.
Mol Ther Oncol. 2025 Aug 9;33(3):201033. doi: 10.1016/j.omton.2025.201033. eCollection 2025 Sep 18.
Boron neutron capture therapy (BNCT) shows potential for the treatment of glioblastoma, the most aggressive form of primary brain tumor. Recently, ferroptosis, a cell death triggered by phospholipid peroxidation, has been identified as an important process in tumor therapy. However, the ferroptosis in BNCT has not been fully explored. To investigate ferroptosis induced by BNCT, U87 and U251 human glioblastoma cell lines were used. The results demonstrated that BNCT led to a significant 3- to 4-fold increase in lipid peroxides and caused approximately 25% cell death through ferroptosis in a three-dimensional (3D) spheroid model, which was employed to reconstruct the cell force interactions. Furthermore, BNCT promoted the upregulation of FACL4, an essential protein that triggers ferroptosis and induces oxidative stress by disrupting the endoplasmic reticulum and mitochondria, respectively. Moreover, we found that the mechanosensitive protein YAP-1, known to facilitate ferroptosis, was upregulated and redistributed within the spheroids after BNCT treatment, and the BNCT-induced ferroptosis was enhanced by 1.5-fold following the pharmacological interruption of cell force. This study represents the first demonstration of ferroptosis in BNCT and showed the influences of mechanotransduction in the regulation of ferroptosis, offering a potential strategy to enhance the efficacy of BNCT from the perspective of cell mechanics.
硼中子俘获疗法（BNCT）在治疗胶质母细胞瘤（原发性脑肿瘤中最具侵袭性的形式）方面显示出潜力。最近，铁死亡，一种由磷脂过氧化引发的细胞死亡，已被确定为肿瘤治疗中的一个重要过程。然而，BNCT中的铁死亡尚未得到充分研究。为了研究BNCT诱导的铁死亡，使用了U87和U251人胶质母细胞瘤细胞系。结果表明，在用于重建细胞力相互作用的三维（3D）球体模型中，BNCT导致脂质过氧化物显著增加3至4倍，并通过铁死亡导致约25%的细胞死亡。此外，BNCT促进了FACL4的上调，FACL4是一种重要蛋白质，分别通过破坏内质网和线粒体引发铁死亡并诱导氧化应激。此外，我们发现，已知促进铁死亡的机械敏感蛋白YAP-1在BNCT治疗后在球体内上调并重新分布，在细胞力受到药理学阻断后，BNCT诱导的铁死亡增强了1.5倍。这项研究首次证明了BNCT中的铁死亡，并展示了机械转导在铁死亡调节中的影响，从细胞力学角度提供了一种增强BNCT疗效的潜在策略。
