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

Abstract

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.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

“…Indeed, HO can be considered as a modulator factor in ferroptosis, also representing a marker of cells’ responsiveness to this type of PCD. Several natural compounds have found to possess strong potential for clinical use as promoters or inhibitors of ferroptosis [ 70 ], but few studies have focused their attention on the involvement of the HO system. Although a substantial amount of data on ferroptosis inhibitors already exist [ 71 ], for inducers such as curcumin, more extensive studies need to be performed.…”

Astragaloside IV attenuates ferroptosis after subarachnoid hemorrhage via Nrf2/HO-1 signaling pathway

“…Ferroptosis is mostly caused by a disturbance of iron homeostasis and accumulation of Lipid ROS in the cytoplasm (Dixon et al, 2012;Ge et al, 2021). The massive hemorrhage causes brain tissue compression and promotes neuronal damage.…”

“…Transcription factor Nrf2 is a classic protective regulator acting to maintain cellular redox homeostasis by mediating the expression of a series of anti-oxidant enzymes and detoxification genes. In the presence of oxidative stress, Nrf2 will be translocated from the cytoplasm to the nucleus, thereby participating in the transcription of a series of ARE-related genes, which are involved in the regulation of iron metabolism, glutathione synthesis, and lipid peroxidation (Ge et al, 2021;Lu et al, 2021). The activation of Nrf2 pathway reduces intracellular iron pool to restore iron homeostasis, limits ROS production, and upregulates SLC7A11 (Dodson et al, 2019;Zhang S. et al, 2021).…”

“…In the presence of oxidative stress, Nrf2 will be translocated from the cytoplasm to the nucleus, thereby participating in the transcription of a series of ARE-related genes, which are involved in the regulation of iron metabolism, glutathione synthesis, and lipid peroxidation (Ge et al, 2021;Lu et al, 2021). The activation of Nrf2 pathway reduces intracellular iron pool to restore iron homeostasis, limits ROS production, and upregulates SLC7A11 (Dodson et al, 2019;Zhang S. et al, 2021). HO-1 is one of the downstream target genes of Nrf2 with cytoprotective and antioxidant properties (Parfenova et al, 2012).…”

“…Many natural compounds have been reported to exhibit therapeutic functions by modulating ferroptosis (Zhang S. et al, 2021;Ge et al, 2021;He et al, 2021). Astragaloside IV (AS-IV), as a newly found glycoside of cycloartane-type triterpene, is the effective component extracted from Astragalus membranaceus (Costa et al, 2019) (Figure 1).…”