METTL3 silenced inhibited the ferroptosis development via regulating the TFRC levels in the Intracerebral hemorrhage progression

Intracerebral hemorrhage (ICH) refers to the hemorrhage caused by the increase and rupture of vascular brittleness in non traumatic brain parenchyma, which has been demonstrated to be closely related to ferroptosis. This study aimed to examine the effects of methyltransferase like 3 (METTL3) on the ferroptosis in the ICH progression. The PC12 cells was stimulated by hemin to establish a ICH model. The cell viability was tested by CCK8 assay. The Fe2+, reactive oxygen species (ROS), and malondialdehyde (MDA) levels were determined by the corresponding commercial kits. The cell death was analyzed by propidium Iodide (PI) staining. The lactylation levels were detected by western blot. M6A dot blot assay was performed to detected the total m6A levels and MeRIP assay was conducted to determine the m6A levels of transferrin receptor (TFRC). We found that the METTL3 and m6A levels were increased in the hemin treated PC12 cells. METTL3 knockdown increased the cell viability and decreased Fe2+, ROS and MDA levels in the hemin treated PC12 cells. The role of METTL3 knockdown in the hemin treated PC12 cells was reversed after TFRC overexpression. Mechanistically, the METTL3 lactylation was increased in the hemin treated PC12 cells, which further enhanced the protein stability and expression of METTL3. The up-regulated METTL3 increased the m6A levels and mRNA expressions of TFRC, which further induced the ferroptosis of the PC12 cells. In conclusion, the up-regulation of METTL3 lactylation enhanced the METTL3 protein stability and expression levels in hemin treated PC12 cells. METTL3 silenced suppressed the ferroptosis development through regulating the m6A levels of TFRC mRNA.