<p>This study aimed to investigate the role of Piezo1 in the immune-inflammatory response during the pathogenesis of ankylosing spondylitis (AS) and its underlying mechanisms. RT-qPCR was used to evaluate the expression levels of Piezo1 and autophagy-related genes in the peripheral blood of AS patients. Correlation analyses were conducted to evaluate associations between Piezo1 expression and clinical characteristics of AS patients. Immunohistochemistry (IHC) and Western blotting were performed to determine the expression of Piezo1 and autophagy-related proteins in the synovium of AS patients. In vitro, the effects of Piezo1 and autophagy on primary monocyte-derived macrophages and fibroblast-like synoviocytes (FLS) from AS patients were investigated using Yoda1 and 3-MA interventions. Modulation of the immune-inflammatory response via the Piezo1-autophagy axis was examined through RT-qPCR, Western blotting, and ELISA. Finally, the role of Piezo1 in immune regulation was further assessed in proteoglycan-induced arthritis (PGIA) model using GsMTx4, a Piezo1 inhibitor. Piezo1 expression was markedly elevated in AS patients compared to healthy controls and showed a positive correlation with disease activity, duration, and autophagy levels. Mechanistically, increased Piezo1 expression induced M1 polarization of monocyte-macrophages, leading to increased autophagy and the upregulation of inflammatory factors. Additionally, Piezo1 enhanced autophagy and IL-6 activation in FLS. In the PGIA model, GsMTx4 inhibited autophagy hyperactivation, significantly reduced the immune-inflammatory response, and exerted a protective effect on spinal bone tissue. Immunofluorescence further confirmed that these effects might be associated with reduced autophagy and inflammatory cytokine expression in macrophages and FLS. These findings highlight the role of Piezo1 in AS pathogenesis, suggesting that Piezo1 may contribute to the immune-inflammatory response in AS through autophagy regulation.</p>