Inhibiting ferroptosis can reduce I/R injury. I/R and ferroptosis were studied in several organs, such as the heart [8,9,10,11,29], kidney [51,66,67,68], brain [69], intestine [8], and liver [70] (Table 1). I/R includes two parts: ischemia and reperfusion. Ischemia means the sudden block of blood supply in an aerobic organ, and reperfusion means the restoration of blood supply. These processes lead to excessive production of ROS and free radicals, which result in the inflammatory cascade, cell injury, and ferroptosis [71].

ROS are central to I/R. Inhibiting ERS, triggered by ROS, can alleviate ferroptosis in diabetes myocardial I/R injury [9]. Compared with nondiabetic hearts, the expression of GPX4 decreases while malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) increases during myocardial I/R injury in diabetic rats. NADPH oxidase (Nox), the main donor of ROS, is responsible for the oxidative stress in diabetic rat hearts, which is closely related to AMPK [75]. It is reported that the inhibition of glutaminolysis reduces the amount of ROS and increases GSH, thus inhibiting ferroptosis in heart I/R injury [76]. Augmenter of liver regeneration (ALR), colocalized with GPX4, possesses the ability to inhibit ferroptosis by decreasing ROS [67].

Other pathways elucidate the role of ferroptosis in I/R. Liproxstatin-1 (Lip-1), a ferroptosis inhibitor, protects heart I/R injury by reducing voltage-dependent anion channel 1 (VDAC1) levels and increasing GPX4 levels [10,11]. Iron homeostasis is also important because a cohort study shows that the ability to rapidly process iron will be impaired during kidney I/R, which leads to ferroptosis in the end [68].

Ferroptosis can also promote the neutrophil’s adhesion to coronary vascular endothelial cells by Toll-like receptors 4 (TLR4)/TIR domain-containing adapter inducing IFN-beta (Trif)/type I IFN signaling pathway, which aggravates inflammation and leads to I/R injury [8]. Additionally, overexpression of miR-214 or silencing plasmacytoma variant 1 (PVT1) could significantly inhibit ferroptosis and reduce brain infarct size in mice [69]. Renal I/R injury can be attenuated by pannexin 1 (PANX1) depletion for a decrease in mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation, which inhibits ferroptosis [66].

The development of heart failure is related to the loss of myocytes and is proven to have a relationship with ferroptosis. In an integrated bioinformatical analysis, Toll-like receptors 4 (TLR4) and NADPH oxidase4 (NOX4) were increased in HF. Knocking down TLR4 and NOX4 can remarkably inhibit myocyte death mediated by ferroptosis [12]. Another mechanism revealing the role of ferroptosis in HF is mixed lineage kinase 3 (MLK3). MLK3 induces ferroptosis by regulating JUN/p53 mediated oxidative stress in chronic HF. miR-351 can inhibit this kind of heart failure by suppressing the expression of MLK3 [77]. Iron is critical to ferroptosis, the homeostasis of which also plays an important role in HF. Disrupting the ferritin heavy chain (Fth) gene in mice leads to HF owing to iron deposition, whereas decreasing cardiac iron in mice by lacking transferrin receptor 1 (Tfr1) also leads to HF [78,79]. Furthermore, people suffering from HF also have decreased Tfr1 and cardiac iron [63].

There are several compounds to treat HF by regulating ferroptosis. Injecting TLR4-siRNA or NOX4-siRNA lentivirus can protect the failing heart via inhibiting ferroptosis. Puerarin, an antioxidant, can inhibit lipid oxidation and iron overload in mice with heart failure induced by isoprenaline [13]. Deferoxamine, a ferroptosis inhibitor, was reported to mitigate HF or cardiac infarction [15]. All the above suggests that ferroptosis might be a promising target for HF.

Atherosclerosis is mainly caused by lipid deposition, endothelial cell damage, the proliferation of VSMC, and transformation of macrophages, and so on [54]. All these processes involve ferroptosis. Lipid deposition, especially PUFAs, is the substrate of the LOX or Fenton reaction, leading to oxidized lipids and inducing ferroptosis. In high-fat diet (HFD)-fed Apo E-/-mice, the administering of Fer-1, a ferroptosis inhibitor, can promote the expressions of SLC7A11 and GPX4, partially inhibit the iron accumulation and lipid peroxidation, as well as increase ox-LDL-induced mouse aortic endothelial cells (MAECs) viability [16]. Moreover, endothelial cells can be damaged by lipid ROS, increasing the endothelial permeability, promoting lipid deposition, and initiating atherosclerosis. In HUVECs, miRNA17-92 overexpression greatly alleviates erastin-induced cell death through the A20-ACSL4 axis [1]. That means inhibiting ferroptosis in endothelial cells can alleviate endothelial damage and reduce the probability of atherosclerosis. Studies showed that the iron level in healthy arterial tissue is less than that in atherosclerotic plaque [91]. Iron overload is also a key point to induce ferroptosis; therefore, restricting iron, especially nontransferrin bound iron (NTBI), a deleterious iron form, is thought to be therapeutic for atherosclerosis by inhibiting ferroptosis [54,92]. Furthermore, iron overload even changes macrophage function, leading it to polarize toward the proinflammatory subtype [58]. This chronic inflammation of the macrophage contributes to the formation of atherosclerotic necrotic core and destabilization of plaque [93]; therefore, ferroptosis can induce atherosclerosis via iron overload and macrophage changes.

Ferroptosis is related to aging because of the role of iron and excess ROS. Iron accumulates with aging as the need for iron decreases as the metabolic rate reduces, and the amount of hemoglobin also decreases with aging [94]. One experiment on rabbits shows that, compared to that of young ones, aged rabbits possess more free iron, released from ferritin, and this leads to further oxidative damage, which may be related to ferroptosis, because the ferroptosis inhibitor, deferoxamine, is protective of this kind of damage [95].

The homeostasis of iron is critical to ferroptosis and the pathogenesis of vascular and ventricular remodeling. One study shows that iron deficiency contributes to vascular remodeling in the pulmonary of rat [96]. On the contrary, another study reports that restricting iron may moderately alleviate hypoxia-induced vascular remodeling in the pulmonary of mice [97]. As for the heart, it is believed that the myocardial iron in the infarct zone is adverse for ventricular remodeling [98]; therefore, the role of iron and ferroptosis in vascular remodeling needs more investigation (Figure 2).