The m6A demethylase FTO suppresses perivascular adipose tissue browning and exacerbates vascular injury via m6A-mediated destabilization of Irx3 mRNA and the IRX3/UCP1 axis

BACKGROUND AND AIMS: Vascular injury triggers perivascular adipose tissue (PVAT) browning, an adaptive response critical for vascular protection, yet its regulatory mechanisms remain unclear. This study aimed to identify key pathways governing PVAT browning and evaluate their therapeutic potential in vascular repair. METHODS: A murine wire-induced femoral artery injury model was combined with bioinformatics, molecular, and cellular experiments. Key analyses included assessing PVAT browning markers, validating IRX3's role in UCP1-mediated browning, and evaluating the m6A demethylase FTO's regulatory effects on IRX3 mRNA stability. RESULTS: Wire-induced femoral artery injury in mice triggered PVAT browning and upregulation of brown-fat markers, improving local adipose morphology and adipokine secretion. In vitro, brown adipocytes protected endothelial cells from LPS-induced apoptosis and inflammation. Integrative bioinformatics identified IRX3 as a key regulator; gain- and loss-of-function studies confirmed IRX3 promoted adipocyte browning and mitochondrial respiration via direct transcriptional activation of UCP1. Mechanistically, the m6A demethylase FTO suppressed IRX3 expression by promoting m6A-dependent Irx3 mRNA degradation, thus impairing browning. Functional rescue showed that IRX3 overexpression reversed the anti-browning effects of FTO. In vivo, local overexpression of IRX3 further enhanced PVAT browning post-injury, reduced neointimal hyperplasia, and ameliorated vascular inflammation and apoptosis. CONCLUSIONS: These findings reveal that FTO acts as a negative epitranscriptomic regulator of PVAT browning and vascular protection through m6A-mediated Irx3 destabilization and the IRX3/UCP1 axis, offering a promising target for cardiovascular therapy.