Astragalus Polysaccharide Suppresses Inflammation and Promotes Apoptosis in Hypertrophic Scars by Suppressing OGT-Mediated Nrf2 O-GlcNAcylation

Abstract

Background: Hypertrophic scars (HS) arise from excessive tissue proliferation during wound healing, with Nrf2 involved, though the underlying mechanism remains unclear. Astragalus polysaccharides (APS) have anti-inflammatory and antioxidant properties, but their therapeutic effects and mechanisms in HS remain unreported. Objectives: This study intends to clarify how APS target protein O-GlcNAcylation to treat HS. Methods: A HS mouse model was established by subcutaneous injection of bleomycin (BLM) in C57BL/6 mice. Histopathology (H&E and Masson staining), ELISA, CCK-8, flow cytometry, western blot, and co-immunoprecipitation were performed to assess pathological changes, cell viability, apoptosis, inflammatory cytokine levels, and protein O-GlcNAcylation. Results: Astragalus polysaccharides treatment significantly inhibited scar formation and reduced inflammatory cytokine levels in HS mice. In human hypertrophic scar fibroblasts (HHSFs), APS suppressed cell viability and inflammation while promoting apoptosis. Mechanistically, APS decreased global O-GlcNAcylation levels and downregulated the protein expression of OGT and Nrf2. Mechanistically, OGT interacted with Nrf2, enhancing its stability via O-GlcNAcylation at S199. Moreover, Nrf2 overexpression reversed APS-induced changes in HHSF viability, inflammation, and apoptosis. Conclusions: This study identifies the OGT-mediated O-GlcNAcylation of Nrf2 as a novel regulatory mechanism in HS progression. By suppressing this axis, APS demonstrates therapeutic potential for HS. These findings highlight O-GlcNAcylation as a promising therapeutic target and support the clinical development of APS for fibrotic skin disorders.