Insights into emerging mechanisms of ferroptosis: new regulators for cancer therapeutics

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.

Keywords: Cancer; Cell death; Ferroptosis; Lipid peroxidation; Nature products.

Fig. 1

Role of organelles in ferroptosis. The mechanism of action of each organelle in the process of ferroptosis

Fig. 2

Ferroptosis inhibitors, inducers, and their mechanisms of action. The common activators and inhibitors of ferroptosis mainly affect ferroptosis through three pathways: the System Xc- pathway, lipid metabolism regulation mechanism, and iron metabolism regulation pathway

Fig. 3

Chemical structures of ferroptosis inducers and inhibitors from TCM

Fig. 4

TCM affects ferroptosis through the System Xc- and GPX4 pathways. The molecular mechanism by which traditional Chinese medicine affects ferroptosis through the System Xc- pathway and the GPX4 pathway

Fig. 5

Possible mechanism of TCM caused ferroptosis. a. TCM regulates ferroptosis through the iron metabolism pathway. b. TCM regulates ferroptosis through the lipid metabolism pathway