m6A methylases that participate in ferroptosis. Ferroptosis is a form of cell death characterized by an accumulation of Fe2+ ions and lipid peroxide overload. The mechanism of ferroptosis is as follows: i) Iron ions are inputted into the cells, converted into divalent iron and accumulate in large amounts, promoting the occurrence of lipid peroxidation through the Fenton reaction; ii) the systemXc-system (SLC3A2+SLC7A11) is presented: The SystemXc−-GSH-GPX4 axis, wherein GPX4 inhibits lipid peroxidation; iii) SLC38A1+SLC1A5: Glutamine enters the cell through glutamine transporters to generate glutamate, which enters the mitochondria and participates in the TCA cycle to generate mitochondrial ROS, thereby promoting ferroptosis. m6A-associated enzymes can participate in the ferroptotic pathway of tumors, thereby regulating tumor progression. METTL3 inhibits ferroptosis by enhancing the stability of SLC7A11 mRNA through YTHDF1 and IGF2BP2, respectively. METTL14, FTO, YTHDF2 and YTHDC2 inhibit SLC7A11, thereby inducing ferroptosis. YTHDC2 can also increase the sensitivity of tumor cells to ferroptosis by inhibiting SLC3A2. Finally, ALKBH5 induces ferroptosis by mediating the m6A-TIAM1-Nrf2/HO-1 signaling pathway, thereby hindering tumor progression. SLC3A2, solute carrier family 3 member 2; METTL3/4, methyltransferase-like 3/4; FTO, fat mass and obesity-associated protein; ALKBH5, α-ketoglutarate-dependent dioxygenase homolog 5; IGF2BP1/2/3, IGF2 binding protein 1/2/3; YTHDF1/2/3, YTH domain family protein 1/2/3; GSH, glutathione; GPX4, GSH peroxidase 4; ROS, reactive oxygen species; m6A, N6-methyladenosine; TIAM1, TIAM Rac1 associated GEF 1; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase 1; NFE2L2, NFE2 like bZIP transcription factor 2; TCA, tricarboxylic acid; TF, transferrin; TFRC, TF receptor
Mechanisms of N6-methyladenosine modification in tumor development and potential therapeutic strategies (Review) (2023)
Xi Pu, et al. Int J Oncol. 2023 Jun;62(6). Figure: F3.
