Dual regulation of inflammation and ferroptosis: An injectable hydrogel targeting macrophages for the treatment of temporomandibular joint osteoarthritis and knee osteoarthritis.

Osteoarthritis is a common progressive inflammatory degenerative joint disease that causes persistent pain and functional disability. Current treatments are insufficient to halt disease progression; therefore, elucidating the underlying molecular mechanisms and developing targeted local drug delivery systems that intervene in critical pathological nodes are of great clinical significance. This study developed a novel injectable hydrogel drug delivery system (DA-HAMA) based on Hyaluronic acid Methacryloyl (HAMA) to achieve local, sustained-release, and targeted delivery of the small-molecule drug Diminazene aceturate (DA) within the osteoarthritic joint cavity. The study first identified Spermidine/spermine N1-acetyltransferase 1 (SAT1) as a key potential target for inflammation and ferroptosis in OA synovial macrophages through bioinformatics analysis. It further demonstrated that its inhibitor DA effectively suppresses macrophage inflammatory responses and ferroptosis processes in vitro. To overcome DA's rapid metabolism and poor targeting, the DA-HAMA hydrogel was developed. This system not only enables stable drug loading and controlled release but also allows mechanical properties to be adjusted by drug loading concentration, demonstrating excellent structural stability and biocompatibility. In complete Freund's adjuvant (CFA)-induced mouse knee OA and rat temporomandibular joint osteoarthritis (TMJOA) models, intra-articular injection of DA-HAMA hydrogel significantly reduced synovial inflammation, decreased inflammatory cell infiltration, inhibited cartilage destruction, and improved subchondral bone microarchitecture. Its therapeutic effects were closely associated with downregulating inducible nitric oxide synthase (iNOS) expression and upregulating glutathione peroxidase 4 (GPX4) expression in synovial macrophages, confirming its dual anti-inflammatory and anti-ferroptotic functions in vivo. In summary, this study systematically elucidates the potential role of DA in alleviating OA by inhibiting SAT1 and regulating macrophage inflammation and ferroptosis pathways, spanning target discovery, molecular mechanisms, delivery system development, and efficacy validation in vivo. More importantly, it successfully develops a DA-HAMA hydrogel tailored for the joint environment, featuring sustained-release properties and mechanical reinforcement effects, providing a novel therapeutic strategy for localized targeted treatment of OA.