METTL3-associated YTHDF1-COX-1 axis is linked to reduced antiplatelet response to aspirin in older adults

Abstract

This study explores the role and mechanism of RNA m6A methylation in reduced antiplatelet response to aspirin in older adults. A total of 34 patients aged ≥60 years routinely receiving 100 mg/d aspirin were enrolled. Based on light transmission aggregometry (LTA), subjects were divided into a low-response group ( n  = 14, platelet aggregation rate (PAR) ≥12 %) and a high-response group ( n  = 20, PAR ≤7 %). Patients with a low aspirin response exhibited higher levels of m6A, accompanied by elevated methyltransferase-like 3 (METTL3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) ( p  < 0.05). Serum levels of prostaglandin H2 (PGH2) and thromboxane B2 (TXB2) were also elevated in the low-response group. Spearman correlation revealed that PAR and PGH2 were positively correlated with both METTL3 and YTHDF1 mRNA, while TXB2 positively correlated with METTL3 mRNA ( p  < 0.05), indicating the association of m6A degree with aspirin response. Mechanistically, METTL3 overexpression in MEG-01 cells enhanced megakaryocyte proliferation and upregulated YTHDF1 , which subsequently increased the translation efficiency of cyclooxygenase 1 (COX-1) mRNA and elevated COX-1 protein. RNA immunoprecipitation confirmed that YTHDF1 directly bound to COX-1 mRNA in a METTL3-dependent manner. The METTL3/ YTHDF1-COX-1 axis may attenuate the antiplatelet efficiency of aspirin by modulating AA metabolism and megakaryocyte function, providing a potential biomarker and target for aspirin low-responsiveness.