METTL3 depletion mitigates hypoxic pulmonary arterial smooth muscle cell over-proliferation via YTHDF2-dependent regulation of FOXO1 mRNA N6-methyladenosine modification: a potential mechanism of hypoxic pulmonary hypertension.

AIMS: To determine the role of METTL3-mediated m6A modification in hypoxic pulmonary arterial smooth muscle cells (PASMCs) over-proliferation and hypoxic pulmonary hypertension (HPH).

MATERIALS AND

METHODS

Human PAH tissues, smooth muscle-specific Mettl3 knockout mice, HPH models, scRNA-seq, hPASMCs culture, MeRIP-qPCR, RIP-qPCR, luciferase assay, and functional assays.

KEY FINDINGS: METTL3 was upregulated in HPH PASMCs. Mettl3 depletion alleviated HPH and suppressed PASMC proliferation via FOXO1 upregulation. METTL3 reduced m6A on FOXO1 3'UTR, decreased YTHDF2 binding, and stabilized FOXO1 mRNA. FOXO1 or YTHDF2 manipulation abolished METTL3-dependent effects.

SIGNIFICANCE: We identify a METTL3-YTHDF2-FOXO1 axis driving PASMC proliferation in HPH, providing a potential therapeutic target.