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

ABSTRACT 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‐ β 1 and IL‐1 β . This model was combined with pharmacological modulation of Sirt1 using EX527 and SRT1720, as well as HIF‐1 α overexpression or empty‐vector lentiviral transduction, to dissect the underlying molecular mechanisms. Mechanistically, Glyasperin F upregulated Sirt1, thereby suppressing the PI3K/Akt/HIF‐1 α pathway, downregulating key glycolytic enzymes (HK2, PFK, PKM2, LDHA), and reducing lactate/ATP production and oxidative stress. HIF‐1 α 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.