Ferroptosis in acute leukemia

Abstract

Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis, pyroptosis, and necrosis. The main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions, lipid peroxidation of cell membrane lipids, and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4 (GPX4). Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders, such as ischemia-reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply studied. This article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting ferroptosis. More importantly, it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.

Figure 1

Timeline of the discovery of important molecules related to ferroptosis. Based on the findings of a large number of basic studies, the formal definition of "ferroptosis" was proposed in 2012. Since then, many studies have revealed the important molecules and mechanisms related to ferroptosis. ACSL4: Acyl-CoA synthetase long-chain family member 4; AlOX12: Arachidonate 12-lipoxygenase; FSP1: Ferroptosis suppressor protein 1; GPX4: Glutathione peroxidase 4; PUFA: Polyunsaturated fatty acid.

Figure 2

The function of the ferroptosis mechanism is to balance oxidative damage and antioxidant defense. The mechanism of ferroptosis mainly involves two parts: oxidative damage and antioxidant defense. When the physiological state of the body changes and oxidative damage increases, ferroptosis and ferroptotic cell death are induced; in contrast, overexuberant antioxidant defense hinders the occurrence of ferroptosis. AA: Arachidonic acid; ACSL4: Acyl-CoA synthetase long-chain family member 4; AdA: Adrenic acid; BH4: Tetrahydrobiopterin; CoQ10: Coenzyme Q10; CoQ12: Coenzyme Q12; FSP1: Ferroptosis suppressor protein 1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; iNOS: Inducible nitric oxide synthase; LOX: Lipoxygenase; NCOA4: Nuclear receptor coactivator 4; NO: Nitric oxide; NRF2: Nuclear factor erythroid 2-related factor 2; PE-AA: Arachidonic acid-phosphatidylethanolamine; PLOOHs: Phospholipid hydroperoxides; PUFA: Polyunsaturated fatty acid; ROS: Reactive oxygen species; SLC3A2: Solute carrier family 3 member 2; TF: Transferrin.

Figure 3

Summary of the mechanisms related to ferroptosis in AML and ALL cells. The interaction of various molecules forms a network of molecular pathways related to ferroptosis. In AML cells, the upregulation of p53 expression by circKDM4C via hsa-let-7b-5p can reduce ferroptosis; also, APR-246 can target the mutant protein p53 in AML and promote the binding of mutant p53 to the target site of DNA to regain its transcriptional activity, the combination of APR-246 with ferroptosis inducers, or the inactivation of SLC7A11 has synergistic anti-leukemic activity in vitro; HMGB1 can regulate Erastin-induced ferroptosis through Ras-JNK/p38 signal pathway; additionally, some drugs or natural abstracts can also induce ferroptosis and help to fight AML. In ALL cells, the ubiquitination of PAQR3 by NRF2 can induce ferroptosis; RSL3 can induce ferroptosis by enhancing the production of ROS and this process can be blocked by LOX inhibitors or ferroptosis inhibitors; HD induces ferroptosis via reducing GSH and GPX4. ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; AMPK: Adenosine monophosphate-activated protein kinase; APR-246: Eprenetapopt; ATLL: Adult T cell leukemia/lymphoma; ATPR: 4-Amino-2-trifluoromethyl-phenyl retinate; DFA: Deferoxamine; DHA: Dihydroartemisinin; DNA: Deoxyribonucleic acid; Fer-1: Ferrostain-1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HD: Hydnocarpin D; HMGB1: High mobility group protein 1; KDM4C: Lysine demethylase 4c; LOX: Lipoxygenases; NRF2: Nuclear factor erythroid 2-related factor 2; PAQR3: Progestin and adipoq receptor family member 3; Ras-JNK: Rat sarcoma-jun N-terminal kinase; ROS: Reactive oxygen species; RSL3: An inhibitor of glutathione peroxidase 4; SLC7A11: Solute carrier family 7 member 11; ub: Ubiquitination.