Polyphenol‐Rich Duhuo Jisheng Decoction Enhances Mesenchymal Stem Cell–Derived Exosome–Mediated Chondroprotection via PI3K/AKT Signaling in Osteoarthritis

Osteoarthritis (OA), a representative chronic degenerative joint disease, is closely associated with chronic inflammation and dysregulated cell survival. Dietary polyphenols are recognized for their protective roles against chronic inflammatory conditions. Duhuo Jisheng Decoction (DHJST), a polyphenol‐rich traditional herbal formula, is widely used for degenerative joint diseases. This study aims to explore the novel mechanisms of DHJST‐derived bioactives in enhancing the chondroprotective potential of mesenchymal stem cell‐derived exosomes. We integrated network pharmacology and machine learning to identify the core AKT‐related targets of DHJST. Bone marrow mesenchymal stem cells (BMSCs) were preconditioned with DHJST‐containing serum to generate enhanced exosomes (DHJST‐Exos), applying to IL‐1β–stimulated rat chondrocytes and a collagenase‐induced OA rat model. The therapeutic efficacy was evaluated via inflammatory markers, extracellular matrix (ECM) homeostasis, and apoptosis assays, with the PI3K/AKT inhibitor Rigosertib used for mechanistic validation. Network pharmacology identified key bioactive polyphenols including wogonin, quercetin, kaempferol, and other polyphenol‐like constituents in DHJST that significantly modulate the PI3K/AKT pathway. DHJST ‐Exos effectively suppressed TNF‐α and IL‐6, reduced MMP‐13 and ADAMTS‐5 levels, and restored COL2A1 and Aggrecan expression. Furthermore, DHJST ‐Exos attenuated chondrocyte apoptosis by regulating the Caspase‐3/Bax/Bcl‐2 axis. Mechanistically, DHJST ‐Exos up‐regulated the expression of hub genes JUN and KDR via AKT phosphorylation, a protective effect that was significantly abrogated by Rigosertib. This study demonstrates that polyphenol‐rich DHJST enhances the therapeutic efficacy of BMSC‐derived exosomes against OA by activating the AKT signaling pathway and its key nodes, JUN and KDR. This synergistic strategy, combining dietary bioactives with exosome‐mediated delivery, represents a promising adjunctive approach for the management of chronic degenerative joint diseases.