Polycaprolactone microspheres promote hyaluronic acid synthesis in fibroblasts via FOXA1 O-GlcNAcylation

Polycaprolactone (PCL) microspheres, widely recognized for their biocompatibility and collagen-stimulating properties, have been employed as skin fillers in plastic surgery. However, their broader impact on the synthesis of other extracellular matrix (ECM) components in the skin remains poorly understood. Hyaluronic acid (HA), a critical ECM constituent, is tightly regulated by multiple factors, including metabolic intermediates and epigenetic modifications. Herein, we confirmed that 6-hydroxyhexanoic acid (6-HHA), degradation metabolite of PCL microspheres, significantly enhances HA synthesis in skin fibroblasts. Specifically, PCL microspheres upregulate the expression of hyaluronic acid synthases (HAS), activate the hexosamine biosynthesis pathway (HBP) in fibroblasts. This metabolic shift leads to elevated levels of O-linked N-acetylglucosamine (O-GlcNAc) and increased O-GlcNAc transferase (OGT)-mediated protein glycosylation (O-GlcNAcylation). Mechanistically, we identify forkhead box A1 (FOXA1) as a key transcriptional regulator of HAS expression. Notably, PCL microspheres facilitate O-GlcNAcylation of FOXA1 at serine 151 (S151) in an OGT-dependent manner, enhancing the transcriptional activity of HAS genes and promoting HA synthesis. Collectively, our findings reveal a novel mechanism by which PCL microspheres stimulate HA production through FOXA1 O-GlcNAcylation, providing new insights into the role of post-translational modification in ECM remodeling in skin aging and skin regeneration.