METTL14 Hinders DCM Progression via Mediating the m6A Methylation of NRG4 in HG-Induced H9C2 Cells.

Diabetic cardiomyopathy (DCM) is a common form of cardiomyopathy that affects the cardiac muscle. It can lead to heart failure and threaten the life of human. Neuregulin 4 (NRG4) is a novel adipose factor released from brown adipose tissues and is considered to play an important role in metabolism, and affects the diabetic cardiomyopathy. N6-Methyladenosine (m6A) modification has been implicated in many bioprocesses. So we aim to explore the role of methyltransferase 14 (METTL14) and NRG4 in the progression of DCM. The high-glucose (HG) could increase the expression of NRG4. In HG-induced H9C2 cells, the up-regulated NRG4 promoted the cell proliferation and GSH levels, and suppressed the cell apoptosis, inflammation factors (IL-1β and IL-6), and Fe and ROS levels. The RMbase database, SRAMP website, and RMvar database predicted that NRG4 had m6A modification site. Western blot assay demonstrated that OE-METTL14 promoted NRG4 expression. METTL3 could bind to NRG4. Besides, METTL14 and IGF2BP1 positively regulated NRG4 by increasing its mRNA stability. In HG-induced H9C2 cells, METTL14 promoted the NRG4 levels and cell proliferation and retarded the cell apoptosis, inflammation and ferroptosis via facilitating expression of NRG4. Besides, the METTL14 overexpression could increase the expression of nuclear factor erythroid 2-related factor 2 (NRF2), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in HG-induced H9C2 cells. METTL14 curbs the progression of DCM via enhancing the m6A methylation of NRG4 in HG-induced H9C2 cells, which can help extend our understanding on the epigenetic regulation of ferroptosis in DCM progression.