Natural flavonoids act as potent ferroptosis inhibitors and their potentials in the treatment of ferroptosis-associated diseases
Lu Liu, Lun Wang, Ying Xiao, Yue Liu, Xianli Meng, Xiaofei Shen
Abstract
Ferroptosis, an iron-dependent cell death characterized by lethal lipid peroxidation, has been involved in the pathogenesis of various diseases, such as ischemia/reperfusion injury, neurodegenerative diseases, and inflammatory disorders. Pharmacological inhibition of ferroptosis represents a promising strategy for the treatment of the above diseases. Flavonoids, a class of natural products found in medicinal plants and functional foods, are known for numerous activities, especially the newly discovered anti-ferroptotic activity. Our review aims to expand our understanding of flavonoids’ anti-ferroptotic activity on multiple biological systems and to highlight the importance of utilizing flavonoids in ferroptosis-associated diseases. A systematic literature search was conducted using Google Scholar, PubMed, Web of Science, ScienceDirect, and Springer Link. The search was conducted using the following keywords: flavonoids, natural products, ferroptosis, mechanism, ischemia/reperfusion injury, neurodegenerative diseases, and inflammatory diseases. The available information was comprehensively studied and compiled. We review the recent advances in molecular mechanisms of ferroptosis and its multiple roles in diverse diseases. We further systematically summarize the inhibitory roles and underlying mechanisms of flavonoids on ferroptosis, and suggest that inhibition of lipid ROS accumulation and labile Fe2+ availability as well as activation of Nrf2 signaling are responsible for ferroptosis inhibition. We also discuss their clinical applications in ferroptosis-related diseases. Taken together, natural flavonoids exhibit a promising treatment prospect for ferroptosis-associated diseases. This review is also expected to not only facilitate the design and development of flavonoid-based ferroptosis inhibitors, but also and the treatment of ferroptosis-related diseases using flavonoid-based therapies.