Novel insights into ferroptosis: Implications for age-related diseases

Abstract

Rapid increase in aging populations is an urgent problem because older adults are more likely to suffer from disabilities and age-related diseases (ARDs), burdening healthcare systems and society in general. ARDs are characterized by the progressive deterioration of tissues and organs over time, eventually leading to tissue and organ failure. To date, there are no effective interventions to prevent the progression of ARDs. Hence, there is an urgent need for new treatment strategies. Ferroptosis, an iron-dependent cell death, is linked to normal development and homeostasis. Accumulating evidence, however, has highlighted crucial roles for ferroptosis in ARDs, including neurodegenerative and cardiovascular diseases. In this review, we a) summarize initiation, regulatory mechanisms, and molecular signaling pathways involved in ferroptosis, b) discuss the direct and indirect involvement of the activation and/or inhibition of ferroptosis in the pathogenesis of some important diseases, and c) highlight therapeutic targets relevant for ARDs.

Ferroptosis as a novel therapeutic target for cardiovascular disease

“…It also proceeds in the absence of the key components of necroptosis, such as MLKL, RIPK1 and RIPK3. Early studies have suggested that regulated forms of cell death contribute significantly to the pathogenesis of CVDs, including cardiomyopathy, MI and HF 65 , 66 . Although it remains unclear whether ferroptosis is an independent form of cell death or whether it acts to amplify necrotic cell death, the molecules that mediate ferroptosis may provide new therapeutic targets for CVDs.…”

Lipid Metabolism and Ferroptosis

“…Ferroptosis is implicated in a variety of human diseases, such as myocardial infarction, atherosclerosis, kidney diseases, liver diseases, and neuronal diseases, as well summarized in recent review articles [ 22 , 97 , 98 , 99 , 100 ]. Numerous ferroptosis inhibitors, including ferrostatin-1, liproxstatin-1, vitamin E analogs, and iron chelators, have been shown to effectively ameliorate disease symptoms in mouse models of each disease [ 22 , 97 , 98 , 99 ]. In this review, we discussed the underlying mechanism of lipid peroxidation in ferroptosis and the various lipid metabolic pathways that control lipid peroxidation and ferroptosis.…”

“…Ferroptosis can be induced by several ferroptosis-inducing compounds (FINs) [ 22 , 23 ]. Erastin is the first identified FIN that inhibits the cystine/glutamate antiporter (system x c − ), thereby resulting in the depletion of glutathione (GSH), a cofactor for GPX4 ( Figure 1 ) [ 16 ].…”

“…Class II FINs such as RSL3, ML162, and ML210 covalently bind to and directly inhibit GPX4, thereby rapidly inducing ferroptosis ( Figure 1 ) [ 24 ]. In addition, numerous compounds, such as FIN56 and withaferin A, have been identified as other classes of FINs [ 22 , 23 ]. In this review, we will focus on lipid metabolism, which governs cellular susceptibility to ferroptosis by regulating the intracellular composition of phospholipids and the process of lipid peroxidation.…”

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

“…However, these measures have limited success, and there are no effective intervention or treatment measures to protect the brain against cell death [169,170]. Accumulating evidence demonstrates that ferroptosis accelerates ischemic stroke, and ferroptosis inhibition can significantly reduce disease severity and facilitate functional recovery [170]. Deferoxamine (DFO), an iron chelator widely used to treat iron overload, reduces the cerebral infarct volume in MCAO rats and suppresses ferroptosis by promoting erythropoietin synthesis and increasing hypoxia-inducible factor-alpha (HIF-α) levels [24].…”