Gas Plasma Exposure Attenuates the Inflammatory Rheumatoid Arthritis‐Like Phenotype of Murine Synoviocytes in Vitro

ABSTRACT Rheumatoid arthritis (RA) is driven by hyperplastic fibroblast‐like synoviocytes (FLS) that adopt a persistent inflammatory and invasive phenotype, often resistant to conventional therapies. Here, we investigated whether cold gas plasma exposure modulates inflammatory FLS (iFLS) in vitro. Primary murine FLS were primed with TNF‐α to induce an inflammatory phenotype and exposed to an argon plasma jet for 30–150 s; argon gas alone served as a control. Gas plasma treatment caused a rapid, dose‐dependent rise in intracellular reactive oxygen species and free thiols, followed by partial resolution by 24 h. This oxidative burst coincided with mitochondrial dysfunction and progressive loss of cell viability. Surviving iFLS exhibited markedly reduced inflammatory features, such as surface levels of ICAM‐1 (CD54), VCAM‐1 (CD106), and Thy‐1 (CD90.2), along with diminished production of IL‐6 and CCL2 at higher doses. Reflecting the impaired expression of inflammation‐associated adhesion molecules. Furthermore, plasma treatment significantly delayed iFLS migration. Together, these findings suggest that cold gas plasma has cytotoxic effects on a subset of iFLS induced by acute oxidative stress, as well as reprogramming surviving iFLS towards a less aggressive phenotype. These in vitro data establish a foundation for further research in synovial explants and arthritis models, as well as for systematic safety testing in non‐inflammatory joint‐resident cells.