Ginkgolide A enhances FoxO1 expression and reduces endoplasmic reticulum stress to mitigate osteoarthritis in mice

•Ginkgolide A delays chondrocyte apoptosis and extracellular matrix degradation.•Ginkgolide A modulates FoxO1-mediated endoplasmic reticulum stress.•Ginkgolide A has the potential to serve as a therapeutic agent for osteoarthritis. This study aimed to investigate the effects of Ginkgolide A (GA) on chondrocytes under oxidative stress and to elucidate its potential molecular mechanisms. Using a destabilization of the medial meniscus (DMM) model in mice and an in vitro osteoarthritis (OA) model induced by tert-butyl hydroperoxide (TBHP) in chondrocytes, we validated the therapeutic efficacy and underlying mechanisms of GA. Potential OA targets of GA were identified through network pharmacology, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Further exploration into the effects on endoplasmic reticulum stress (ERS), apoptosis, extracellular matrix (ECM) degradation, and Forkhead Box O1 (FoxO1) related pathways was conducted using Western blotting, immunofluorescence, TUNEL staining, flow cytometry, X-ray, micro-computed tomography (Micro-CT) analysis, and histological staining. The results demonstrated that GA upregulated FoxO1 expression and inhibited ERS-related signaling pathways, thereby reducing apoptosis and ECM degradation. In conclusion, GA significantly alleviated OA symptoms both in vitro and in vivo, suggesting its potential as a therapeutic agent for OA.