Geniposidic acid from ginger-processed Eucommiae Cortex alleviates rheumatoid arthritis by modulating macrophage lactylation induced by exosomes from inflammatory fibroblast-like synoviocytes.

Eucommiae Cortex (EC), a Traditional Chinese health food product, is known for its anti-inflammatory, antioxidant, and hepatoprotective effects, with promising potential in treating rheumatoid arthritis (RA). This study used liquid chromatography-tandem mass spectrometry (LC-MS) to profile the bioactive compounds of ginger-processed EC (G-EC), focusing on its absorbed constituents and metabolic fate in vivo. Network pharmacology identified geniposidic acid (GPA) as a key bioavailable compound in G-EC, potentially alleviating RA. In vivo, GPA significantly improved RA symptoms. Additionally, exosomes from inflammatory fibroblast-like synoviocytes (FLSs) (LPS-exo) promoted M1 macrophage polarization, glycolytic activation, and synovial inflammation. GPA inhibited glycolysis, reduced M1 polarization induced by LPS-exo, and downregulated H3K56la histone lactylation. Mechanistic analysis suggested these effects involve the regulation of ATP-citrate lyase (ACLY) and Histone deacetylase 6 (HDAC6) expression. This study supports the therapeutic potential of GPA in RA and provides a foundation for further clinical research.