Targeting ferroptosis and ferritinophagy: new targets for cardiovascular diseases

Abstract

Cardiovascular diseases (CVDs) are a leading factor driving mortality worldwide. Iron, an essential trace mineral, is important in numerous biological processes, and its role in CVDs has raised broad discussion for decades. Iron-mediated cell death, namely ferroptosis, has attracted much attention due to its critical role in cardiomyocyte damage and CVDs. Furthermore, ferritinophagy is the upstream mechanism that induces ferroptosis, and is closely related to CVDs. This review aims to delineate the processes and mechanisms of ferroptosis and ferritinophagy, and the regulatory pathways and molecular targets involved in ferritinophagy, and to determine their roles in CVDs. Furthermore, we discuss the possibility of targeting ferritinophagy-induced ferroptosis modulators for treating CVDs. Collectively, this review offers some new insights into the pathology of CVDs and identifies possible therapeutic targets.

Keywords: Cardiovascular disease; Ferritinophagy; Ferroptosis; Iron; Therapeutic target.

Fig. 1. Ferroptosis: lipid peroxidation and iron overload. Upon iron overload, Fe³⁺-bound transferrin binds to transferrin receptor and forms endosome, where Fe³⁺ turns to Fe²⁺ and subsequently induces Fe²⁺ overload in the cytosol ( Yu et al., 2021 ). Iron overload induces ROS production, mediating lipid peroxidation via the Fenton reaction ( Tang et al., 2020 ). Consequently, lipid peroxidation induces membrane damage and ferroptosis. Mammalian cells are apt to prevent lipid peroxidation. Cystine/glutamate antiporter systems activate GPX4 and resist lipid peroxidation and ferroptosis ( Lee JY et al., 2021 ; Li FJ et al., 2022 ). Under some conditions, these anti-ferroptosis systems are unable to exert normal function, which makes cells susceptible to ferroptosis. Moreover, proper induction of ferritinophagy complements Fe²⁺ by mediating ferritin degradation, thus as a protective way. However, when excessive ferritinophagy, Fe²⁺ is over accumulated and induces lipid peroxidation and ferroptosis. SLC: solute carrier family; TF: transferrin; TP53: tumor protein p53; CD44v: cluster of differentiation 44 variant; MUC1: mucin 1; GSH: glutathione; GSR: glutathione reductase; GSSG: oxidized glutathione; NADPH/NADP⁺ ‍: nicotinamide adenine dinucleotide phosphate; ER: endoplasmic reticulum; EIF2A: eukaryotic initiation factor 2α; EIF2AK3: EIF2A kinase 3; ATF4: activating transcription factor 4; HSPA5: heat shock 70 kDa protein 5; GPX4: glutathione peroxidase 4; MT1G: metallothionein 1G; FTH1: ferritin heavy chain 1; HO-1: heme oxygenase 1; ROS: reactive oxygen species; PLA2G2A: phospholipase A2 group IIA; ACSL4: long-chain acyl-coenzyme A (CoA) synthetase 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; ALOX15: arachidonate 15-lipoxygenase; CSD1: the first cold-shock domain; GST: glutathione S-transferase; CYP2D6: cytochrome P450 family 2 subfamily D member 6; NFE2L2: nuclear factor erythroid 2-related factor 2; IREB2: iron-responsive element-binding protein 2; TFRC: transferrin receptor; PCBP: poly(rC)‍-binding protein; PROM2: prominin 2; NCOA4: nuclear receptor coactivator 4.

Fig. 2. Modulation of NCOA4-mediated ferritinophagy by the intercellular level of iron. Under iron deficiency, PCBP1 recruits iron to ferritin, containing heavy and light chains. NCOA4 binds to ferritin and transfers it to the nascent autophagosome through unknown mechanisms ( Santana-Codina and Mancias, 2018 ). Subsequent fusion of the autophagosome and lysosome leads to ferritinophagy, degradation of ferritin, and induction of iron release. Increased ferritinophagy is positively correlated with increased ROS and ferroptosis. Iron is also critical in iron homeostasis of the liver and in brain development. During iron-abundant conditions, HERC2 binds to NCOA4 and mediates its proteasomal degradation, leading to decreased NCOA4 level, ferritinophagy, and intracellular iron level ( Mancias et al., 2015 ). PCBP1: poly(rC)‍-binding protein 1; NCOA4: nuclear receptor coactivator 4; HERC2: HECT and RLD domain containing E3 ubiquitin protein ligase 2; Ub: ubiquitin; ROS: reactive oxygen species.

Fig. 3. Potential induction of ferritinophagy in CVDs. Ferritinophagy and its induced ferroptosis are involved in the pathogenesis of several CVDs. For instance, NCOA4-mediated ferritinophagy is activated in TAC-induced pressure overload failed heart tissues (Omiya et al., 2021). Apelin-13 induces ferritinophagy and cardiac hypertrophy (Yang et al., 2022). Administration of baicalin relieves ferritinophagy and injured cardiac function in heart I/R rats. LPS affects the mitochondrial shrinkage and condensation, induces crista reduction, mediates membrane density and rupture, and further induces ferroptosis. ZnONPs induce endothelial cell injury by promoting ferroptosis in vitro and in vivo (Qin X et al., 2021). CVDs: cardiovascular diseases; NCOA4: nuclear receptor coactivator 4; TAC: transverse aortic constriction; I/R: ischemia/reperfusion; ZnONPs: ZnO nanoparticles; FTH1: ferritin heavy chain 1; LPS: lipopolysaccharide.