Activation of Sirt1 by Glyasperin F Suppresses PI3K/Akt/HIF-1α Signaling and Inhibits Glycolytic Metabolism to Ameliorate Pathology in Rheumatoid Arthritis-Associated Interstitial Lung Disease

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe extra-articular complication with limited treatment options. This study identified Glyasperin F, a flavonoid derived from licorice and dried ginger decoction, as a potent inhibitor of glycolytic reprogramming in RA-ILD. Using a murine model combining collagen-induced arthritis and bleomycin-induced pulmonary fibrosis, we demonstrated that Glyasperin F significantly alleviated joint inflammation and pulmonary fibrosis. An in vitro inflammatory-fibrotic model was established by co-stimulating MRC-5 human lung fibroblasts with TGF-β1 and IL-1β. This model was combined with pharmacological modulation of SIRT1 using EX527 and SRT1720, as well as HIF-1α overexpression or empty-vector lentiviral transduction, to dissect the underlying molecular mechanisms. Mechanistically, Glyasperin F upregulated SIRT1, thereby suppressing the PI3K/Akt/HIF-1α pathway, downregulating key glycolytic Enzymes (HK2, PFK, PKM2, LDHA), and reducing lactate/ATP production and oxidative stress. HIF-1α overexpression reversed these therapeutic effects. This study suggests that Glyasperin F has the potential to serve as a natural candidate compound for the regulation of glycolytic metabolism in the intervention of RA-ILD.