Effect of FKBP5 inhibitor SAFit2 on fibro-adipose progenitor cells isolated from facial infiltrating lipomatosis

Facial infiltrating lipomatosis (FIL) is a congenital disorder characterized by unilateral facial enlargement. Although next-generation sequencing has revealed that the pathogenesis of FIL is associated with phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations, the underlying molecular mechanisms remain undetermined. We found that the adipose tissue in FIL patients demonstrated tissue infiltration accompanied by adipocytes hypertrophy and increased lipid accumulation. All FIL derived fibro-adipose progenitor cells (FIL-FAPs) harboured PIK3CA mutations. Compared to FAPs obtained from normal subcutaneous adipose tissue, FIL-FAPs exhibited a greater capacity for adipogenesis. Suppression of PIK3CA resulted in a reduction in the adipogenic potential of FIL-FAPs. Through single cell sequencing, we find that FIL-FAPs had higher expression of FKBP5. Inhibiting FKBP5 can impair the adipogenic capacity of FIL-FAPs. We also verified that PI3K-AKT pathway regulating FKBP5 expression. To find the downstream target of FKBP5, we performed RNA-seq of FIL-FAPs treated with FKBP5 inhibitor SAFit2 in DMSO or DMSO alone. Overall design: To explore the gene expression alterations in FIL-ADSCs after SAFit2 treatment, we applied SAFit2 to FIL-FAPs isolated from three different patients. By utilizing RNA sequencing, we compared the gene expression profiles between SAFit2-treated and untreated FIL-FAPs.