Zhang Erhao, Wang Yichao, Zhang Hongli, Li Xiaomin, Su Yijing, Cui Jianan, Xu Rui, Mao Xue, Sang Mengmeng, Lin Zenghua, Zhou Xiaorong
Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, PR China.
Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, PR China.
Free Radic Biol Med. 2025 May 1;235:231-247. doi: 10.1016/j.freeradbiomed.2025.04.052.
Triple-negative breast cancer (TNBC) has no expression on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), resulting in an ineffective treatment using current therapeutic therapies. As a heterogeneous disease, the notable refractory, high recurrence rate and unfavorable prognosis facilitate some researches to further elaborate novel insights into the biology of TNBC and formulate the precision treatment. Ferroptosis is a unique regulated-cell-death modality characterized by the excessive accumulation of the lipid peroxides on cellular membranes in an iron-dependent manner. Resveratrol (RES), a natural antioxidant that possesses biological activities, has various potential benefits for many diseases through regulating the cell activity. RES has been reported to markedly inhibit the tumor progression, yet its role in ferroptosis pathway of TNBC and the underlying mechanism remain unclear. In this study, we found that RES suppressed cell viabilities, consisting of cell migration, cell colony formation, and induced the cell apoptosis, along with mitochondrial structure damage, intracellular iron overload, increasing reactive oxygen species (ROS) and lipid peroxidation accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion, interestingly, which was reversed by ferroptosis inhibitors. Next, the protein level of GPX4 was significantly suppressed in RES-treated TNBC cells in vitro and in vivo, facilitating the cancer cell ferroptosis. Our data confirm that RES suppresses GPX4 protein by increasing the NEDD4L-mediated ubiquitination attributed from the enhanced interactions between NEDD4L and GPX4 through the inhibition of the ERK1/2/SGK1/NEDD4L/GPX4 pathway in vitro and in vivo. In conclusion, our study identified the mechanism by which RES could exert ferroptosis in TNBC, finally providing a novel strategy for TNBC treatment.
三阴性乳腺癌（TNBC）在雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）上均无表达，导致目前的治疗方法对其无效。作为一种异质性疾病，TNBC显著的难治性、高复发率和不良预后促使一些研究进一步深入探究TNBC的生物学特性并制定精准治疗方案。铁死亡是一种独特的程序性细胞死亡方式，其特征是细胞膜上脂质过氧化物以铁依赖的方式过度积累。白藜芦醇（RES）是一种具有生物活性的天然抗氧化剂，通过调节细胞活性对多种疾病具有多种潜在益处。据报道，RES可显著抑制肿瘤进展，但其在TNBC铁死亡途径中的作用及潜在机制仍不清楚。在本研究中，我们发现RES抑制了包括细胞迁移、细胞集落形成在内的细胞活力，并诱导细胞凋亡，同时伴有线粒体结构损伤、细胞内铁过载、活性氧（ROS）增加、脂质过氧化积累、丙二醛（MDA）生成以及谷胱甘肽（GSH）耗竭，有趣的是，这些现象可被铁死亡抑制剂逆转。接下来，在体外和体内接受RES处理的TNBC细胞中，GPX4的蛋白水平均显著降低，从而促进癌细胞发生铁死亡。我们的数据证实，RES通过在体外和体内抑制ERK1/2/SGK1/NEDD4L/GPX4途径，增强NEDD4L与GPX4之间的相互作用，增加NEDD4L介导的泛素化，从而抑制GPX4蛋白。总之，我们的研究确定了RES在TNBC中发挥铁死亡作用的机制，最终为TNBC治疗提供了一种新策略。
