Xing Zhengcao, Wei Xiangyun, Fan Qiuju, Zhao Dongfeng, He Jianli, Cheng Jinke
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochem Biophys Res Commun. 2025 Jul 1;768:151959. doi: 10.1016/j.bbrc.2025.151959. Epub 2025 May 7.
Glioblastoma multiforme (GBM) is a common and highly malignant brain tumor characterized by heterogeneity, invasiveness, and resistance to therapy. Inducing ferroptosis in GBM represents a promising therapeutic strategy that inhibits angiogenesis. Natural ingredients in anti-tumor adjuvants are increasingly reported to promote cell death with fewer side effects. Salvia miltiorrhiza Bunge has been widely proven to have significant anti-tumor activity, but its mechanism remains unclear and not deeply understood. This study aimed to investigate the mechanisms by which the compound cryptotanshinone (CTS) induces cell death in glioblastoma (GBM). Our findings revealed that cryptotanshinone, a lipophilic compound, exhibited the most significant anti-tumor activity against GBM. We observed that cryptotanshinone triggered ferroptosis in GBM cells both in vitro and in vivo. RNA sequencing analysis (RNA-seq) revealed that cryptotanshinone led to the upregulation of heme oxygenase 1 (HMOX1), a key protein that facilitates the release of iron ions, which is essential for the induction of ferroptosis. Knocking down HMOX1 could restore ferrous ion levels and Glutathione peroxidase 4 (GPX4) expression to antagonize GBM ferroptosis induced by cryptotanshinone. An in vivo study also showed that cryptotanshinone inhibited GBM growth and upregulated HMOX1 expression without significant side effects. Mechanistically, we found that cryptotanshinone, acting as a protein-protein interaction (PPI) inhibitor of nuclear factor erythroid 2-related factor 2 (NRF2) and Kelch-like ECH-associated protein 1 (KEAP1), promoted the dissociation of NRF2 from KEAP1, enhancing NRF2 nuclear translocation and the transcription of HMOX1. Together, our results revealed that cryptotanshinone is a novel ferroptosis inducer for GBM treatment.
多形性胶质母细胞瘤（GBM）是一种常见的高度恶性脑肿瘤，具有异质性、侵袭性和对治疗的抗性。在GBM中诱导铁死亡是一种有前景的抑制血管生成的治疗策略。越来越多的研究报道，抗肿瘤佐剂中的天然成分能以较少的副作用促进细胞死亡。丹参已被广泛证明具有显著的抗肿瘤活性，但其机制仍不清楚，尚未得到深入了解。本研究旨在探讨隐丹参酮（CTS）诱导胶质母细胞瘤（GBM）细胞死亡的机制。我们的研究结果表明，隐丹参酮这种亲脂性化合物对GBM具有最显著的抗肿瘤活性。我们观察到，隐丹参酮在体外和体内均可诱导GBM细胞发生铁死亡。RNA测序分析（RNA-seq）显示，隐丹参酮导致血红素加氧酶1（HMOX1）上调，HMOX1是促进铁离子释放的关键蛋白，对诱导铁死亡至关重要。敲低HMOX1可恢复亚铁离子水平和谷胱甘肽过氧化物酶4（GPX4）表达，拮抗隐丹参酮诱导的GBM铁死亡。体内研究还表明，隐丹参酮可抑制GBM生长并上调HMOX1表达，且无明显副作用。机制上，我们发现隐丹参酮作为核因子红细胞2相关因子2（NRF2）和 Kelch样ECH相关蛋白1（KEAP1）的蛋白质-蛋白质相互作用（PPI）抑制剂，促进NRF2与KEAP1解离，增强NRF2核转位及HMOX1转录。总之，我们的结果表明隐丹参酮是一种用于GBM治疗的新型铁死亡诱导剂。
