Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

Abstract

Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.

Colorectal cancer: Identifying molecular subtypes and establishment ofing a novel prognostic model based on metabolic plasticity- and ferroptosis-related gene signatures

“…Metabolic plasticity confers a survival advantage to cancer cells for using nutrients, rapidly producing ATP, synthesizing biomass, and balancing reactive oxygen species [28]. Metabolic plasticity and ferroptosis are common metabolic pathways in tumor cells and are extensively studied in other diseases [29][30][31]. GO analysis showed that the abnormal expression of key genes in MPFDEGs primarily involves immune receptor activity and cytokine receptor binding, considering molecular functions.…”

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis‑related genes

“…However, under the stimulation of chronic ischemia, the excessive deposition of collagen-rich extracellular matrix determines the pathological remodeling of the myocardium and causes an increase in mechanical strain in the border zone, which may lead to expansion of the fibrotic area, decreased tissue compliance and increased cardiac afterload (50)(51)(52)(53)(54). Existing research indicates that regulating FRGs can effectively reduce cardiac injury, fibrosis and pathological remodeling during ischemia (55). In the present study, the DEFRGs were found to be enriched in iron metabolism and the HIF-1 signaling pathway.…”

Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells

“…Disruption of iron homeostasis results in iron overload, where excess ferrous iron (Fe 2+ ) induces lipid peroxidation via the Fenton reaction, leading to a redox imbalance [ 28 – 30 ]. A growing body of evidence underscores the pivotal role of ferroptosis in the pathogenesis of numerous cardiovascular diseases by disrupting normal cellular functions [ 31 – 33 ]. For instance, oxidized low-density lipoprotein (ox-LDL) has been implicated in the induction of endothelial dysfunction and ferroptosis through the modulation of ADM transcription and the activation of the AMPK signaling cascade [ 34 ].…”