Ferroptosis is a novel iron-dependent mode of death induced by elastin and Ras selective lethal 3 (RSL3) (1). Different from apoptosis, classic necrosis, autophagy, and other forms of cell death. The morphological features of ferroptosis are reduced cell size, increased mitochondrial membrane density, and decreased cristae. It is characterized by the induction of lipid peroxides (LPO) accumulation dependent on iron ions and reactive oxygen species (ROS). Polyunsaturated fatty acid (PUFA) in phospholipids, REDOX active iron, and repair defects of LPO are three characteristics of ferroptosis, which determine the sensitivity of tumor cells to ferroptosis (2, 3). Targeted small molecule substances reduce the antioxidant glutathione (GSH) levels or glutathione peroxidase 4 (GPX4) by acting on specific targets in the cell, which leads to the accumulation of intracellular ROS and lipids. In the synergistic action of iron, peroxidation induces ferroptosis (4, 5). Cystine/glutamate antiporter (system Xc-) exists on the cell surface to maintain REDOX homeostasis, promote the entry of cystine into the cell, and then reduce it to cysteine, which removes excess glutamate from the cell and provides the raw material for intracellular GSH synthesis. Meanwhile, GSH is an essential substrate for the degradation of LPO by glutathione peroxidase 4 (GPX4). When the GSH synthesis pathway is inhibited, LPO accumulates, and ferroptosis occurs (6, 7). Ferroptosis requires GSH depletion, decreased glutathione peroxidase 4 (GPX4) activity, and the inability to metabolize lipid peroxides through GPX4-catalyzed glutathione reductase reaction, thereby destroying the integrity of the cell membrane (8). Initially, Dixon et al. suggested that ferroptosis is mainly regulated by ribosomal protein L8 (RPL8), iron response element binding protein 2 (IREB2) at the gene level. ATP synthase F0 complex subunit C3 (ATP5G3), tetratricopeptide repeat domain 35 (TTC35), Regulation of citrate synthase (CS) and acyl-CoAsynthetase family member 2 (ACSF2) (1). Later, many studies have shown that many genes/proteins and molecular are involved in this particular cell death process, such as cyclooxygenase 2(PTGS2) (9), p53 (10), nuclear factor E2-related factor 2(Nrf2) (11), phosphatidylethanolamine binding protein 1(PEBP1) (12) and miRNA (13). In addition to these key regulators, the onset of ferroptosis is associated with excess glutamate, an increase in the intracellular iron concentration, or the handling of small-molecule substances such as elastin, RSL3, and others in Table 1 .

In recent years, with the in-depth study of the mechanism of ferroptosis, ferroptosis has been found in a variety of tumor cells, including breast cancer (20), lung cancer (1), liver cancer (21), kidney cancer (22) and brain tumors (23). In 2015, Jiang et al. found that p53 is essential in regulating ferroptosis, and this study found that ferroptosis contributes to embryonic development (10). Leukemia and lymphoma are the most common hematological malignancies. The main treatment methods are chemotherapy and stem cell transplantation. Although the treatment level of stem cell transplantation has been dramatically improved in recent years, its application has certain limitations (24). At the same time, the remission rate of chemotherapy is low, and there has been no substantial progress in recent years. Therefore, exploring treatment options that will benefit patients is still necessary. As one of the cell death modes, ferroptosis is a popular research direction in tumor research and treatment (25, 26). The known ferroptosis inducers can be divided into the following two categories. The first category includes Erastin, sulfasalazine, glutamate. Which can act through system xc-. The second class includes RSL3 and DP17, which can directly inhibit glutathione peroxidase activity (GPX). Unlike other ferroptosis inducers that usually mediate a single pathway, Erastin can mediate multiple molecules with efficient, rapid, and long-lasting effects (5, 27). In addition, depending on the mechanism of ferroptosis, many molecules have been identified as ferroptosis inhibitors, including ferrostatin-1(Fer-1, inhibiting lipid ROS) (1), deferoxamine (DFO, chelating iron) (1). Examples include deferoxamine (DFO, chelating iron) (1), zileuton (inhibiting 5-lipoxygenase) (28), and the newly discovered FINO2(iron oxide) (14). This article reviews the research progress of ferroptosis in hematological malignancies, and the main inducers, regulators, and inhibitors of ferroptosis in hematological malignancies, as shown in Table 1 .

Iron is a nutrient that promotes cell metabolism, proliferation, and growth. Iron ions can gain and lose electrons. They are the active sites of many iron- and heme-containing enzymes in the body, such as mitochondrial enzymes related to respiratory complexes, enzymes related to DNA synthesis and cell cycle, and enzymes related to detoxification functions (such as peroxidase and catalase); the ability to freely gain and lose electrons allows iron to participate in redox reactions and form free radicals (15). Through the Fenton reaction, hydrogen peroxide reacts under the catalysis of ferrous iron to generate reactive oxygen species (16) Reactive oxygen species can causelipid and protein damage and oxidative DNA damage, including DNA base modification and DNA strand breaks, inducing mutations and promoting the occurrence and progression of tumors (17). In recent years, evidence has shown that ROS are essential for health. Under physiological conditions, generating low levels of ROS is considered a signaling molecule. On the other hand, abnormal iron accumulation, ROS overproduction, and ROS buffer system dysfunction can cause many chronic diseases. Therefore, the chronic accumulation of ROS is involved in many diseases. Moreover, excessive ROS production induces oxidative damage of biomolecules, leading to aging, cancer, and many other diseases (18). Many studies have shown that iron metabolism disorders are related to the occurrence of a variety of diseases, including hereditary hemochromatosis, myocardial ischemia-reperfusion injury, neurodegenerative diseases, and even cancer (19, 29, 30). Specifically, excessive intracellular iron levels can mediate carcinogenesis due to its pro-oxidative properties and DNA-damaging effects. At the same time, tumor cells acquire large amounts of iron to maintain rapid growth and proliferation (31). Under normal homeostasis, transferrin binds to free iron in the circulation, and metabolic iron in the body is maintained at a steady state. When iron overload occurs in the body, serum transferrin binding is close to saturation, and there is non-transferrin-bound iron (NTBI) in circulation (6, 32, 33). However, excessive iron can increase intracellular ROS content through the Fenton reaction, thus promoting ferroptosis (16). In vitro treatment of mouse primary hepatocytes and bone marrow-derived macrophages (BMDMs) with ferric ammonium citrate (FAC) significantly increased lipid peroxidation, decreased NADPH, and decreased cellular viability. These changes were reversed by ferroptosis inhibitors and iron chelators (34). In addition, the team also found that the Slc7a11-/- mouse model did not cause ferroptosis under basal iron conditions. The high-iron diet caused increased non-transferrin-bound iron in mice, decreased GSH levels, and increased ROS levels, indicating that iron-induced ferroptosis differs from that induced by erastin. Nuclear receptor coactivator 4 (NCOA4) is a selective receptor for the selective autophagy flip of ferritin in ferroptosis Hou et al. knocked out NCOA4 in PANC1 cells, which reduced the level of intracellular divalent iron. Ferroptosis is induced by erastin, and the level of iron is increased in the cells overexpressing NCOA4 by transfection, and the level of ferroptosis is increased. Therefore, the increase of intracellular iron caused by the degradation of ferritin mediated by NCOA4 participates in ferroptosis (35). The exosomes secreted by GPX4 inhibitor-treated cells contain a large amount of ferritin (36).

Compared with normal hematopoietic cells, leukemic cells have altered iron uptake, storage, and efflux and an altered iron transporter-hepcidin regulatory axis ( Figure 1 ) (17). Although iron and the reactive oxygen species generated by its catalysis are crucial to maintaining the balance of the hematopoietic system, the accumulation of iron and the subsequent abnormal increase in reactive oxygen species can disrupt various biological functions of hematopoietic stem cells (HSCs) (37), including quiescence, self-renewal, and multilineage differentiation potential. Excessive ROS promotes cell senescence and apoptosis and impairs self-renewal ability and tumor formation, similarly, too much iron can lead to changes in the tumor microenvironment that promote cancer cell ferroptosis (38, 39). In addition, iron is crucial to the development of leukemia because iron-dependent ribonucleotide reductase is required for DNA synthesis to maintain the rapid proliferation of leukemia cells (40–42). In addition, iron overload induces apoptosis of neighboring NK cells, CD4+ T cells, and CD8+ T cells while simultaneously increasing the ratio of regulatory T cells, allowing leukemia cells to evade immune system attack (43, 44). In addition, unlike malignant tumors of other systems, patients with hematological malignancies require repeated blood transfusions due to normal erythropoiesis and chemotherapy, resulting in increased iron load in the body. Excessive iron and ROS can promote the malignant transformation of hematopoietic stem cells by consuming smoke NADPH oxidase (NOX) and GSH (39). In myelodysplastic syndromes, ROS-induced DNA damage may increase patients’ risk of leukemia (38). These results indicate that excessive iron promotes ferroptosis through the ROS pathway, and changes in intracellular iron levels mediated by the ferritin metabolism pathway are also closely related to ferroptosis. Regulating the homeostasis of iron metabolism alters the susceptibility of AML cells to ferroptosis, and disease progression in leukemia also increases iron accumulation in patients.

Ferroptosis is a cell death mediated by various small molecules, such as erastin and RSL3. It is affected by GPX4, GSH metabolism, iron metabolism, and other pathways. Its occurrence is often accompanied by the accumulation of ROS and other substances, which can further lead to the peroxidation of cell membrane lipids. The specific mechanism of ferroptosis needs further study. The study of cell death mode is still an essential link in overcoming the tumor treatment problem. In recent years, ferroptosis has been more popular in tumor research. Many studies have shown that the sensitivity of leukemia and lymphoma cells to ferroptosis can be regulated by changing the concentration of ferroptosis-inducing molecules, the balance between intracellular ROS level and cell death, and the level of intracellular iron metabolism, to achieve the goal of eliminating leukemia and lymphoma cells. Studies have also found that many compounds are closely related to the ferroptosis of tumor cells, and the level of ferroptosis inducers is related to the prognosis of the disease. In addition to the existing iron chelators and targeted iron metabolism-related proteins, treating redox imbalance disorders targeting high intracellular iron levels also has broad application prospects in treating leukemia. The application of ferroptosis and ferromacrophages as a new ferroptosis therapy in leukemia has just begun. With the rapid development of nanotechnology, efforts have been made to exploit the therapeutic advantages of iron-based nanoparticles. The Magnetic field can not only concentrate nanoparticles but also promote the production of intracellular ROS, thus exerting an anti-leukemia effect. The progression of blood system tumor diseases and the changes brought about by treatment will also affect the ferroptosis process. There will be expected to be more related studies to provide new ideas for treating leukemia and lymphoma.

(I) Conception and design: CC, YLiu, ZD. (II) Administrative support: None. (III) Provision of study materials or patients: YLiu, ZD, JH, TL, JZ, WY, YLi. (IV) All authors performed data collection and summary. (V) Data analysis and interpretation: Not applicable. (VI) Manuscript writing: All authors. All authors contributed to the article and approved the submitted version.