Demethylase FTO attenuates atherosclerotic plaque via upregulating ABCA1 and ABCG1 expression by targeting ATG5

Abstract

N6-methyladenosine (m6A), the predominant internal modification in eukaryotic mRNAs, has emerged as a significant epigenetic regulator in atherosclerosis; however, its precise mechanistic contributions remain inadequately elucidated. The present study demonstrated that the m6A demethylase fat mass and obesity-associated (FTO) regulates autophagy, lipid metabolism and plaque vulnerability by targeting autophagy related 5 (ATG5). FTO knockdown resulted in reduced ATG5 expression, thereby suppressing autophagy and downregulating ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette sub-family G member 1 (ABCG1). The regulation of ATG5 expression by FTO occurs through direct binding to its transcripts as well as m6A-mediated mechanisms. Increased m6A modification on ATG5 mRNA following FTO silencing enhanced its recognition by YTH domain-containing family 1, leading to transcript degradation and diminished protein levels. Consequently, autophagy and cholesterol efflux pathways were inhibited. In vivo experiments revealed that specific FTO knockdown compromised plaque stability and impaired ATG5-mediated autophagy, in addition to downregulating ABCA1 and ABCG1. These findings highlighted the FTO-ATG5-ABCA1/ABCG1 axis as a critical regulator of autophagy and lipid homeostasis in atherosclerosis.