Daidzin Inhibits Endoplasmic Reticulum Stress by Regulating FoxO1 Expression to Alleviate Osteoarthritis Progression

ABSTRACT Endoplasmic reticulum stress (ERS) and chondrocyte apoptosis are recognized as critical pathological factors in the development of osteoarthritis (OA). Daidzin (DDZ), an isoflavone derived from soybean, exhibits antioxidant, anticancer, and anti‐atherosclerotic properties. This research seeks to investigate the therapeutic potential and primary mechanisms of Daidzin using a murine Destabilization of the Medial Meniscus instability model and a TBHP‐induced in vitro OA chondrocyte model. Through network pharmacology analysis, potential OA‐related targets of Daidzin were identified. A mouse OA model was established and randomly divided into five groups: sham operation group, DMM group, DMM + 5 mg/kg DDZ group, DMM + 10 mg/kg DDZ group, and DMM + 3 mg/kg indomethacin group, which were examined histologically by hematoxylin and eosin (HE), Safranine O (SO), and histochemistry, and histologically by X‐ray and CT techniques Imaging. The effect of Daidzin on chondrocyte endoplasmic reticulum stress, apoptosis, extracellular matrix (ECM) breakdown, and Forkhead Box O1 (FoxO1)‐related signaling pathways was further investigated using various experimental techniques. The findings indicate that Daidzin upregulates FoxO1 level, inhibits endoplasmic reticulum stress, and attenuates both chondrocyte apoptosis and ECM degradation. The results suggest that Daidzin exerts therapeutic effects in OA models through both in vivo and in vitro experiments, highlighting its possibility as a viable treatment option for osteoarthritis.