Insights into emerging mechanisms of ferroptosis: new regulators for cancer therapeutics
Siyi Xu, Shuangshuang Yin, Lei Wang, Hao Zhong, Hong Wang, Haiyang Yu
Abstract
Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides, which has been implicated in the pathogenesis of various diseases, and therapeutic agents targeting ferroptosis are emerging as promising tools for cancer treatment. Current research reveals that ferroptosis-targeted therapies can effectively inhibit tumor progression or delay cancer development. Notably, natural product-derived compounds—such as artemisinin, baicalin, puerarin, quercetin, kaempferol, and apigenin—have demonstrated the ability to modulate ferroptosis, offering potential anti-cancer benefits. Mechanistically, ferroptosis exhibits negative glutathione peroxidase 4 (GPX4) regulation and demonstrates a positive correlation with plasma membrane polyunsaturated fatty acid (PUFA) abundance. Moreover, the labile iron pool (LIP) serves as the redox engine of ferroptosis. This review systematically analyzes the hallmarks, signaling pathways, and molecular mechanisms of ferroptosis, with a focus on how natural product-derived small molecules regulate this process. It further evaluates their potential as ferroptosis inducers or inhibitors in anti-tumor therapy, providing a foundation for future clinical translation. This review demonstrates the three main pathways involved in ferroptosis: the System Xc- pathway, lipid metabolism regulation mechanism, and iron metabolism regulation pathway. These three pathways work together to increase the intracellular ROS content and lipid peroxidation level, thereby inducing ferroptosis in cells. Additionally, the 7 most widely used and well-studied of the 17 active components derived from traditional Chinese herbs mentioned in the article are introduced, and their specific mechanisms for modulating ferroptosis are described.