Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds

Abstract

Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc^- system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis' involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.

Keywords: Xc− system; cancer; ferroptosis; glutathione peroxidase; iron; lipid peroxidation; natural antioxidants.

Figure 1

Ferroptosis pathway. Ferroptosis may be triggered by transferrin endocytosis linked to transferrin receptor 1 (TfR1). After endocytosis, transferrin releases Fe³⁺ which is reduced in Fe²⁺. Ferrous iron-mediated Fenton reaction increases ROS such as hydroxyl radical that react with membrane lipids inducing lipid peroxidation. Lipid peroxidation is also alimented via LOX action which oxidizes PUFA, generating the corresponding hydroperoxide derivatives which, in turn, react with other membrane lipids. Lipid peroxidation may be regulated by GPx4, which converts hydroperoxides in H₂O and lipid peroxides into their respective alcohols via oxidation of GSH into its disulfide form GSSG. GSH levels are maintained by system Xc⁻, which mediates the exchange of extracellular glutamate and intracellular cystine required for its synthesis.

Figure 2

Ferroptosis-related diseases and pathophysiological implications. Ferroptosis can be associated with different diseases affecting different body districts, such as nervous system, digestive system, respiratory system, circulatory system, urinary system, and immune system.