Ferroptosis Inhibitors as Potential New Therapeutic Targets for Cardiovascular Disease

Abstract

Ferroptosis is a novel form of programmed cell death that arises as a result of an increase in iron levels. Ferroptosis is implicated in a number of cardiovascular diseases, including myocardial infarction (MI), reperfusion damage, and heart failure(HF). Because cardiomyocyte depletion is the leading cause of patient morbidity and mortality, it is critical to thoroughly comprehend the regulatory mechanisms of ferroptosis activation. In fact, inhibiting cardiac ferroptosis has the potential to be a useful therapeutic method for cardiovascular disorders. The iron, lipid, amino acid, and glutathione metabolism strictly governs the beginning and execution of ferroptosis. Therefore, ferroptosis can be inhibited by iron chelators, free radical-trapping antioxidants, GPX4 (Glutathione Peroxidase 4) activators, and lipid peroxidation (LPO) inhibitors. However, the search for new molecular targets for ferroptosis is becoming increasingly important in cardiovascular disease research. In this review, we address the importance of ferroptosis in various cardiovascular illnesses, provide an update on current information about the molecular mechanisms that drive ferroptosis, and discuss the role of ferroptosis inhibitors in cardiovascular disease.

Exploring the Use of Intracellular Chelation and Non-Iron Metals to Program Ferroptosis for Anticancer Application

“…The combination of a low pH (pH 5.4) and a high ATP concentration (5 mM) resulted in virtually 100% dissociation of Zn(II) and 5-Fu from a 0.4 mg/mL amount in less than 30 min and shrank the diameter of particles to 5 nm. This dissociation was correlated with turning on of 19 F-MRI [65].…”

“…Nanoparticle vehicles have been designed to enhance 5-Fu cellular delivery and its immune response, but efforts have less than ideal. Due to the Zn(II)-binding capabilities of 5-Fu, Zhang et al rationalized that a Zn(II) 5-Fu polymeric-like network could be developed that would combine the cell intrusive properties of both Zn(II) and 5-Fu and also facilitate the 19 F-magnetic resonance imaging (MRI) "turn-on" potential due to the high drug payload within cancer cells [65]. A Zn(II)-5-Fu metallodrug network (Zn-Fu MNs; Figure 9) was created through a straightforward process of mixing Zn(NO 3 ) 2 and fluorouracil by means of sonication.…”

“…Great insight into the manifestation of ferroptosis has been garnered through the discovery/development of ferroptosis inducers and inhibitors. The inducers consist of erastin (system Xc − system inhibitor), the covalent GPX4 inhibitors (ML162 and (1S, 3R)-RSL3), mevalonate pathway (responsible for GPX4 maturation) inhibitors (FIN56 and analogues), promoter of iron oxidation ((−)-FINO 2 ), and temozolomide (DMT-1 enhancer) [18,19]. The inhibitors include the iron chelators (deferoxamine, deferiprone, deferasirox), free radical-trapping antioxidants, GPX4 activators, and LPO inhibitors [19].…”

“…The inducers consist of erastin (system Xc − system inhibitor), the covalent GPX4 inhibitors (ML162 and (1S, 3R)-RSL3), mevalonate pathway (responsible for GPX4 maturation) inhibitors (FIN56 and analogues), promoter of iron oxidation ((−)-FINO 2 ), and temozolomide (DMT-1 enhancer) [18,19]. The inhibitors include the iron chelators (deferoxamine, deferiprone, deferasirox), free radical-trapping antioxidants, GPX4 activators, and LPO inhibitors [19]. To date, this diverse set of chemical tools has yet to produce a clinical anticancer drug with the specific intention of inducing ferroptosis.…”

Design, synthesis, and evaluation of novel ferrostatin derivatives for the prevention of HG-induced VEC ferroptosis

“…There is a wealth of evidence demonstrating that the inhibition of ferroptosis can alleviate VEC dysfunction and subsequently delay the onset of related diseases, such as diabetic cardiovascular complications. 14,[29][30][31][32][33][34] Therefore, these ferroptosis inhibitors 8, 11, 12, and 16-19 were examined to determine their effectiveness in inhibiting HG-induced VEC ferroptosis. In this study, HUVECs were stimulated with 30 mM HG for 24 h to mimic the in vivo vascular environment of diabetes.…”