Cartilage extracellular matrix regeneration with 10-gingerol via KEAP1-NRF2-ARE axis for osteoarthritis therapy.

Osteoarthritis (OA) is characterized by oxidative stress, inflammation, and apoptosis, leading to an imbalance between cartilage extracellular matrix (ECM) synthesis and degradation. Gingerols can regulate multiple biological activities, indicating their therapeutic potential for OA. The present study investigated the feasibility, efficacy, and mechanism of gingerols for OA therapy. Regarding feasibility, gingerol exhibited antioxidant, anti-inflammatory, and antiapoptotic activities for OA therapy, while 10-G exhibited most potent effects among the three gingerols. Regarding efficacy, 10-G upregulated the expression of genes associated with ECM assembly and downregulated the expression of genes involved in ECM disassembly. Mechanistically, 10-G promoted NRF2 nuclear translocation; enhanced antioxidant gene expression; inhibited the phosphorylation of ERK, JNK, P38, RELA, and IKBA; and reduced the expression levels of TP53 and CDKN1A, thereby decreasing the production of inflammatory cytokines and apoptotic regulators. Furthermore, KEAP1 was identified as the direct target of 10-G, with NRF2 confirmed as the key regulatory target. This study demonstrates that 10-G mitigates oxidative stress, inflammation, and apoptosis through the KEAP1-NRF2-ARE axis and simultaneously restores ECM balance to promote cartilage regeneration, establishing its potential as a novel candidate for OA therapy.