Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products

Ferroptosis, a newly discovered form of regulatory cell death (RCD), has been demonstrated to be distinct from other types of RCD, such as apoptosis, necroptosis, and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and is inhibited by iron chelators and lipophilic antioxidants. This process is regulated by specific pathways and is implicated in diverse biological contexts, mainly including iron homeostasis, lipid metabolism, and glutathione metabolism. A large body of evidence suggests that ferroptosis is interrelated with various physiological and pathological processes, including tumor progression (neuro)degenerative diseases, and hepatic and renal failure. There is an urgent need for the discovery of novel effective ferroptosis-modulating compounds, even though some experimental reagents and approved clinical drugs have been well documented to have anti- or pro-ferroptotic properties. This review outlines recent advances in molecular mechanisms of the ferroptotic death process and discusses its multiple roles in diverse pathophysiological contexts. Furthermore, we summarize chemical compounds and natural products, that act as inducers or inhibitors of ferroptosis in the prevention and treatment of various diseases. Herein, it is particularly highlighted that natural products show promising prospects in ferroptosis-associated (adjuvant) therapy with unique advantages of having multiple components, multiple biotargets and slight side effects.

Automated summary

Ferroptosis is a newly discovered form of regulatory cell death that is distinct from other types of cell death. It is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and can be inhibited by iron chelators and lipophilic antioxidants. This process is implicated in various biological contexts, including iron homeostasis, lipid metabolism, and glutathione metabolism. Ferroptosis is closely related to physiological and pathological processes such as tumor progression, (neuro)degenerative diseases, and hepatic and renal failure. There is a need for the discovery of novel compounds that can modulate ferroptosis, despite the existence of some experimental reagents and approved clinical drugs with anti- or pro-ferroptotic properties. This review discusses the molecular mechanisms of ferroptotic death and its roles in different pathophysiological contexts, as well as chemical compounds and natural products that can induce or inhibit ferroptosis for the prevention and treatment of various diseases. It emphasizes the promising prospects of natural products in ferroptosis-associated therapy due to their multiple components, multiple biotargets, and slight side effects.