Xu Jiaojiao, Bai Xue, Dong Keting, Du Qian, Ma Ping, Zhang Ziqian, Yang Jianhong
Medical School, University of Chinese Academy of Sciences, No. 1, Yanqi Lake East Road, Huairou District, Beijing 101408, China.
Cancers (Basel). 2025 Feb 21;17(5):739. doi: 10.3390/cancers17050739.
BACKGROUND/OBJECTIVES: Ferroptosis, a type of programmed cell death, is mainly associated with disruptions in iron metabolism, imbalances in the amino acid antioxidant system, and the build-up of lipid peroxides. Triple-negative breast cancer (TNBC) has a dismal prognosis. Since activating ferroptosis can suppress breast cancer cell proliferation, it holds promise as a novel therapeutic target for breast cancer patients. Thus, the objective of this study was to clarify the mechanism of ferroptosis in TNBC, aiming to find new treatment strategies for TNBC patients.
We screened out the differential genes related to ferroptosis in TNBC after GluOC treatment based on the whole-genome sequencing results. At the cellular level, we conducted explorations using techniques such as quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, fluorescence staining, and siRNA transfection. Moreover, we further verified the role of GluOC in inhibiting ferroptosis in TNBC through in vivo experiments using nude mice.
The results showed that GluOC enhanced glutathione expression levels by inducing SLC7A11 accumulation via the specific signaling pathway. Additionally, GluOC increased ATP production and tricarboxylic acid flux resistance to ferroptosis through SLC38A1. Overall, GluOC coordinately regulated SLC7A11 and SLC38A1 to inhibit ferroptosis in TNBC.
This study elucidated the mechanism of GluOC in inhibiting ferroptosis in TNBC. The findings not only provided new insights into ferroptosis but also potentially offered new concepts for the development of future anticancer therapies, which may contribute to improving the treatment of TNBC patients.
背景/目的：铁死亡是一种程序性细胞死亡，主要与铁代谢紊乱、氨基酸抗氧化系统失衡以及脂质过氧化物积累有关。三阴性乳腺癌（TNBC）预后较差。由于激活铁死亡可抑制乳腺癌细胞增殖，因此有望成为乳腺癌患者的新型治疗靶点。因此，本研究的目的是阐明TNBC中铁死亡的机制，旨在为TNBC患者寻找新的治疗策略。
基于全基因组测序结果，我们筛选出了经GluOC处理后TNBC中与铁死亡相关的差异基因。在细胞水平上，我们使用定量实时聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法、荧光染色和小干扰RNA（siRNA）转染等技术进行了探索。此外，我们通过使用裸鼠进行体内实验，进一步验证了GluOC在抑制TNBC铁死亡中的作用。
结果表明，GluOC通过特定信号通路诱导溶质载体家族7成员11（SLC7A11）积累，从而提高谷胱甘肽表达水平。此外，GluOC通过溶质载体家族38成员1（SLC38A1）增加三磷酸腺苷（ATP）生成和三羧酸通量，抵抗铁死亡。总体而言，GluOC协同调节SLC7A11和SLC38A1以抑制TNBC中的铁死亡。
本研究阐明了GluOC抑制TNBC铁死亡的机制。这些发现不仅为铁死亡提供了新的见解，还可能为未来抗癌治疗的发展提供新的概念，这可能有助于改善TNBC患者的治疗。
