Polystyrene microplastics activate NF-κB/MAPK signaling in synovial fibroblasts, promoting inflammation and joint destruction in rheumatoid arthritis.

Microplastics (MPs) are emerging environmental contaminants, yet their impact on autoimmune diseases such as rheumatoid arthritis (RA) remains unclear. We report that polystyrene microplastics (PS-MPs) are detectable in synovial fluid samples from RA patients and that exposure to 5 μm PS-MPs directly promotes the pathogenic activation of RA fibroblast-like synoviocytes (RA-FLSs), key effector cells in synovial inflammation and joint destruction. High-resolution imaging confirmed PS-MPs internalization into the cytoplasm of RA-FLSs, accompanied by cytoskeletal changes and mitochondrial cristae disruption indicative of intracellular stress. PS-MPs exposure activated NF-κB and MAPK (JNK/p38) signaling and induced the expression of IL-6, IL-8, CCL2, MMP3, MMP9, NAMPT, and TWIST1. These changes coincided with enhanced migration, invasion, and monocyte adhesion via increased VCAM-1 and ICAM-1. In vivo, chronic PS-MPs exposure aggravated inflammation in CFA-induced arthritis, with fluorescent particles accumulating in inflamed synovium. In humanized SCID co-implantation model, PS-MPs-treated RA-FLSs triggered greater cartilage erosion and macrophage infiltration. Importantly, pharmacologic inhibition of NF-κB and p38, as well as treatment with Ginsenoside Compound K (GCK), significantly reduced PS-MPs-induced cytokine production in vitro. Together, these findings demonstrate that MPs can directly activate synovial fibroblasts and aggravate RA pathology. This study identifies MPs as a previously unrecognized environmental cofactor in autoimmune joint disease.