Effect of Ferrostatin-1 on temporomandibular joint synovitis induced by abnormal flow fluid shear stress: An in vitro...

Synovitis of the temporomandibular joint (TMJ), a prevalent degenerative joint disease, plays an important role in the pathogenesis of TMJ osteoarthritis. This pathological condition arises from abnormal mechanical loading that induces a chronic low-grade inflammation within the synovial microenvironment through ferroptotic processes. Our research explores the impact of flow fluid-induced shear stress (FFSS) on ferroptosis in fibroblast-like synoviocytes (FLSs) and elucidates the relationship between mechanical overload and the development of TMJ synovitis. Experimental findings revealed progressive alterations in cellular morphology accompanied by significant elevations in intracellular ferrous ion (Fe^2 +) concentrations and reactive oxygen species (ROS) levels with increasing FFSS intensity (all p < 0.05). Quantitative analysis showed upregulated expression of pro-inflammatory cytokines (IL-1β, IL-18), matrix-degrading enzymes (MMP-3, MMP-13), and ferroptosis-related markers (ACSL4, Nrf2), while antioxidant defense components (GPX4, system Xc-) were downregulated (all p < 0.05). Pharmacological inhibition using Ferrostatin-1 (Fer-1) significantly attenuated intracellular Fe²⁺ and ROS accumulation. The treatment group demonstrated reduced expression of IL-1β (p < 0.05) and ACSL4 (p < 0.001), with concomitant upregulation of GPX4 (p < 0.05) and Nrf2 (p < 0.001), though IL-18 modulation did not reach statistical significance (p > 0.05). These results establish that mechanical overload initiates ferroptosis in FLSs, driving inflammatory responses and extracellular matrix degradation through elevated Fe²⁺ and ROS production, ultimately contributing to TMJ synovitis pathogenesis. Our investigation provides novel mechanistic insights into FFSS-mediated ferroptosis in synovial cells, presenting foundational evidence for developing targeted therapeutic strategies that modulate this cell death pathway to enhance clinical management of TMJ synovitis.