Tryptophan Metabolic Dysregulation Drives Immune Activation and Cartilage Degradation in Osteoarthritis: Functional Validation Integrated with Transcriptomic and Single-Cell RNA Sequencing

Osteoarthritis (OA) is a common chronic degenerative joint disease characterized by complex immune and metabolic abnormalities. However, the role of amino acid metabolism in OA has remained insufficiently elucidated. In this study, we systematically explored the potential role of tryptophan metabolism abnormalities in the pathogenesis of OA. Analysis of transcriptomic data and single-cell RNA sequencing from OA cartilage revealed enhanced gene expression associated with tryptophan transport and activation of the kynurenine pathway. In particular, we identified the key metabolic enzymes IDO1 and TDO2 and detected a chondrocyte subpopulation enriched in metabolic gene expression. Further validation in an IL-1β–stimulated chondrocyte model demonstrated that the accumulation of kynurenine and its toxic metabolites (3-hydroxykynurenine and quinolinic acid), both under inflammatory stimulation and with exogenous supplementation, was characterized as upregulation of matrix degradation markers. These findings suggested that tryptophan metabolic dysregulation was not merely a concomitant feature of OA but also served as a metabolic mechanism driving immune activation and cartilage damage. Overall, this study provided a new perspective on the immunometabolic remodeling process in OA and proposed the kynurenine pathway as a potential therapeutic target.