Metformin Induces Apoptosis and Ferroptosis of Ovarian Cancer Cells Under Energy Stress Conditions

作者：Yulun Wu, Ziying Zhang, Minhui Ren, Yao Chen, Jingying Zhang, Jiarui Li, Feng Gao, Yongli Bao, Yanxin Huang, Xiaoguang Yang, Zhenbo Song · 发表于：Cells · 年份：2025 · DOI：10.3390/cells14030213 · 被引用次数：20 · 研究领域：Cancer, Lipids, and Metabolism、Ferroptosis and cancer prognosis、Metabolism, Diabetes, and Cancer

As ovarian cancer progresses, increased glucose use causes a glucose shortage in the tumor microenvironment. Therefore, it is crucial to find drugs that can effectively kill cancer cells in this energy stress setting. Here, we propose an effective therapeutic strategy that combines nutrient restriction with metformin to combat tumors. This study investigated the effects of metformin on ovarian cancer cells under energy stress conditions, mimicking the nutrient-deprived tumor microenvironment. We revealed that Metformin (10 mM) significantly reduced cell viability and proliferation under glucose deprivation conditions. Furthermore, it enhanced apoptosis and ferroptosis, as demonstrated by alterations in apoptotic protein expression and elevated levels of lipid reactive oxygen species (ROS), malondialdehyde (MDA), lipid peroxidation (LPO), and Fe2+. Transcriptional profiling revealed significant alterations in genes related to iron homeostasis and oxidative phosphorylation. Moreover, Metformin was found to induce mitochondrial dysfunction without affecting mitochondrial DNA or the expression of enzymes in the tricarboxylic acid (TCA) cycle, resulting in decreased ATP production and compromised activities of the respiratory chain complexes. The direct interaction between metformin and the NDUFB4 subunit in mitochondrial complex I was corroborated through the application of cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. In vivo,...