Natural products and immune-cell responses in osteoarthritis: mechanisms, evidence maturity, and translational gaps.

Osteoarthritis (OA) is increasingly recognized as an immune-associated whole-joint disorder characterized by chronic low-grade inflammation, which contributes to joint degeneration, structural deterioration, and persistent pain. Innate and adaptive immune cells, including macrophages, T cells, neutrophils, and mast cells, participate in OA pathogenesis by releasing pro-inflammatory cytokines, reactive oxygen species, and matrix-degrading enzymes, as well as by interacting with chondrocytes, synovial fibroblasts, and subchondral bone cells. Natural products, because of their multi-target pharmacological properties, have emerged as potential modulators of this complex immune microenvironment. This review critically appraises current evidence on natural-product interventions modulating OA-associated immune-cell responses, with particular emphasis on mechanistic evidence, evidence maturity, and translational potential. It further compares evidence across immune-cell populations to identify shared mechanisms, population-specific differences, and key translational gaps. Macrophage- and T-cell-associated responses have the most developed evidence base, with relatively consistent evidence supporting modulation of M1-like/M2-like macrophage phenotypes and the T helper 17 (Th17)/regulatory T (Treg) cell balance. Neutrophil- and mast-cell-associated responses represent emerging or auxiliary areas of evidence, as these immune-cell populations may amplify inflammation and pain through reactive oxygen species production, neutrophil extracellular trap formation, degranulation, and inflammatory mediator release. Evidence for B cells, dendritic cells (DCs), and natural killer (NK) cells remains limited; therefore, these immune-cell populations should currently be regarded as potential research directions rather than established therapeutic targets. Most available data derive from