OBJECTIVE: Ferroptosis is a non-apoptotic cell death mechanism driven by reactive oxygen species (ROS) and iron. Its significance in inflammatory arthritis is well-established, but its role in rheumatoid arthritis (RA) remains uncertain. This study aimed to clarify the mechanisms through which curcumin-mediated photodynamic therapy (CUR-PDT) triggers ferroptosis in RA fibroblast-like synoviocytes (FLSs). METHODS: In vivo studies using a collagen-induced arthritis (CIA) rat model evaluated CUR-PDT effects on joint edema, synovial inflammation, and fibrosis through paw volume measurements and H&E and Masson's trichrome staining. The expression of Nrf2, xCT, and GPX4 in FLSs was assessed via ELISA and immunohistochemistry. In vitro, MH7A cells treated with TNF-α were analyzed for viability, proliferation, invasion, and migration through various assays. Mitochondrial potential and morphology were examined using JC-1 staining and transmission electron microscopy (TEM). Ferroptosis biomarkers, including ROS, malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and Fe RESULTS: The CUR-PDT therapy markedly reduced joint inflammation and collagen deposition in the synovial tissue of CIA rats. It effectively alleviated both inflammation and hyperplasia. Moreover, this therapy facilitated ferroptosis within the synovial tissue. In vitro analyses indicated that CUR-PDT diminished the proliferation and viability of FLSs, resulting in increased ROS levels in the cells. This cascade initiated ferroptosis, as evidenced by decreased glutathione, heightened iron concentrations, mitochondrial shrinkage, and reduced mitochondrial membrane potential. Crucially, the expression of xCT and GPX4 was significantly lowered. Interestingly, knocking down the Nrf2 gene amplified this effect, leading to an even greater reduction in xCT and GPX4 expression. In this context, RA-FLSs exhibited more pronounced ferroptotic traits, including diminished proliferation, invasion, and migration. CONCLUSIONS: This study elucidated a mechanism by which CUR-PDT triggers ferroptosis in FLSs through the downregulation of the Nrf2-xCT-GPX4 signaling cascade, thereby effectively hindering the progression of RA and emphasizing the importance of targeting Nrf2 in disease advancement.