Securidaca inappendiculata Extract Mitigates Joint Damage in Collagen‐Induced Arthritis Rats Through Modulation of the SIRT1/HIF‐1α/Glycolysis Pathway

Abstract

ABSTRACT Securidaca inappendiculata (SI) Hassk. is a traditional Chinese herbal medicine commonly used in Southern China for the treatment of rheumatoid arthritis (RA). However, its exact mechanism of action remains unclear. In this study, we evaluated the therapeutic effects of the SI‐derived compound 1,7‐dihydroxy‐3,4‐dimethoxyxanthone (XAN) in a collagen‐induced arthritis (CIA) rat model by measuring paw thickness, joint morphology, and histopathological changes. In vitro, cytotoxicity of XAN on RAW 264.7 macrophages was assessed using the Cell Counting Kit‐8 (CCK‐8) assay. Additional experiments, including real‐time PCR, immunofluorescence, glycolytic metabolism analysis, Western blotting, and dual‐luciferase reporter assays, were conducted to investigate the mechanisms underlying the anti‐inflammatory effects of XAN. Results showed that XAN significantly alleviated arthritis severity in CIA rats. In RAW 264.7 cells, lipopolysaccharide (LPS) enhanced glycolysis and upregulated NAMPT and HIF‐1α expression, whereas SIRT1 levels were reduced. XAN treatment reversed these effects by suppressing glycolysis in LPS‐induced macrophages, indicating that its anti‐inflammatory activity involves modulation of cellular energy metabolism. Further mechanistic studies revealed that XAN attenuates inflammation by regulating the SIRT1/HIF‐1α/glycolysis signaling axis in macrophages. These findings underscore the role of energy metabolism in macrophage polarization and suggest that targeting this pathway may represent a promising therapeutic strategy for RA.