Facial infiltrating lipomatosis (FIL) is a rare congenital deformity caused by excessive accumulation of adipose tissue. The typical pathological feature is the hyperproliferation of mature unencapsulated adipocytes that infiltrate adjacent muscles and glands [1]. Facial enlargement caused by lipomatosis and the destruction of maxillofacial anatomy can severely impair the patient's appearance as well as functions such as chewing, swallowing, and vision [2]. Currently, surgery is the main strategy for treating FIL, but the postoperative recurrence rate exceeds 50 % [3]. Therefore, elucidating the molecular mechanisms in FIL pathogenesis is crucial for developing precision-targeted therapeutic interventions.

The underlying causes of FIL were poorly understood until recent studies identified PIK3CA somatic mutations across various tissues of affected individuals [4]. This gene encodes the p110α subunit of class IA PI3K, an enzyme whose hyperactive mutant forms amplify PI3K signaling. Such enhanced activity drives excessive phosphorylation of key effectors like AKT and mTOR, leading to pathological overstimulation of the PI3K-AKT-mTOR axis - a critical regulator of cellular proliferation, viability and expansion [5]. Our previous studies revealed that PIK3CA hotspot mutations lead to more severe clinical phenotypes [6], and hyperactivation of the PI3K-AKT pathway can upregulate FKBP5 expression to promote adipogenesis [7]. However, the precise mechanism through which FKBP5 enhances adipogenic differentiation has not yet been fully elucidated.

N6-methyladenosine (m6A) is the most prevalent internal modification identified in eukaryotic messenger RNAs (mRNAs) and has a major influence on adipogenesis [8]. The m6A modification process is orchestrated by a group of enzymes: 'writers' such as METTL3, METTL14, and WTAP; 'erasers' like fat mass and obesity-associated protein (FTO) and ALKBH5; and 'readers' including YTH domain-containing proteins (YTHDF1/2/3), and insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) [9]. This post-transcriptional modification plays a crucial role in various aspects of RNA metabolism, including mRNA splicing, stability, translation, and nuclear export. Consequently, m6A modifications have attracted increasing interest due to their potential involvement in the development of human diseases [10].

Solute carrier family 7 member 11 (SLC7A11), a component of the SLC7 amino acid transporter family, plays a crucial role in cellular metabolism by facilitating the uptake of cystine and the export of glutamate [11]. The import of cystine into cells is swiftly followed by its reduction to cysteine, a vital component that acts as the limiting factor in the biosynthesis of the antioxidant glutathione (GSH) [12]. SLC7A11 expression directly modulates the intracellular GSH/GSSG ratio, with a decreased ratio demonstrating adipogenesis-promoting effects [13,14]. Nevertheless, the underlying molecular mechanisms remain elusive.

In this study, we identified a novel FKBP5-FTO-m6A regulatory axis in FIL pathogenesis. We found that FK506-binding protein 51 (FKBP5), upregulated by PI3K-AKT signaling, positively regulated FTO expression in FIL-ASPCs, where FTO showed relatively high expression levels. Mechanistically, FTO reduced the m6A modification of SLC7A11 thereby diminishing the stability regulation of SLC7A11 by IGF2BP1, which subsequently downregulated the expression of SLC7A11/xCT in FIL-ASPCs. This led to reduced cysteine uptake and a decreased GSH/GSSG ratio, impairing SIRT6 activity and resulting in increased enrichment of H3K9ac at the promoter regions of adipogenic genes PPARG, CEBPA, and FABP4. This promoted chromatin openness and enhanced their expression.