Hyperactivation of the m6A demethylase FTO to down-regulate SLC7A11/xCT-mediated redox homeostasis and epigenetic remodeling in facial infiltrating lipomatosis.

Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by excessive adipose tissue accumulation and infiltration, leading to severe functional and aesthetic impairments. Current surgical interventions face high recurrence rates and complications, necessitating exploration of molecular mechanisms driving FIL. N⁶-methyladenosine (m⁶A) RNA modification plays an essential role in modulating RNA stability and contribute to the regulation of adipogenesis. However, the detailed mechanism by which m⁶A regulator regulates the pathogenesis of FIL remains unclear. We focused on FTO-mediated m⁶A demethylation and evaluated FTO expression in FIL adipose tissues and adipose stem and progenitor cells (ASPCs) using Western blotting, qPCR, immunohistochemistry, and single-cell RNA sequencing. The regulatory mechanism of FTO on SLC7A11 was explored via MeRIP-seq, RIP-qPCR, and luciferase reporter assays. In vivo effects were evaluated using xenograft, NAC gavage, and AAV8-mediated SLC7A11 overexpression models. The mechanisms by which SLC7A11 influenced adipogenesis were investigated through ATAC-seq, ChIP-qPCR, and enzyme activity assays. FTO was upregulated in FIL tissues and ASPCs, correlating with reduced m⁶A levels, enhanced adipogenesis, and disease severity. Mechanistically, FTO decreased m⁶A modification of SLC7A11, impairing IGF2BP1-mediated stabilization and reducing SLC7A11 expression. This lowered cystine uptake and GSH/GSSG ratio, inhibiting SIRT6 activity and elevating H3K9ac at promoters of adipogenic genes (PPARG, CEBPA, FABP4), thereby enhancing chromatin openness and transcriptional activation. In vivo, SLC7A11 overexpression impaired adipogenic effects. Modulating GSH/GSSG ratios via NAC or BSO validated the redox-epigenetic axis in regulating adipogenesis. Our findings collectively demonstrate that FTO drives FIL progression by m⁶A-dependent suppression of SLC7A11, disrupting redox balance and regulating SIRT6-H3K9ac-mediated epigenetic reprogramming to promote adipogenesis. Targeting the FTO/SLC7A11/GSH/SIRT6 axis offers a promising therapeutic strategy for FIL.