Activation of the NRF2 signaling pathway mitigates arthrofibrosis by suppressing myofibroblast ferroptosis through oxidative stress regulation

Arthrofibrosis, a debilitating chronic disorder marked by restricted joint mobility and functional impairment, is driven by pathological fibroblast activation involving dysregulated proliferation and cell death dynamics. Although fibroblast death is pivotal in the fibrosis process, the specific mechanisms remain undisclosed. Our preceding investigation identified the intriguing occurrence of oxidative stress activation during arthrofibrosis progression. In this study, employing single-cell RNA sequencing, we further substantiate that fibroblasts undergo ferroptosis during arthrofibrosis development. We validate that ferroptosis contributes to fibroblast demise in both arthrofibrosis-afflicted rats and fibroblasts treated with transforming growth factor β. Additionally, we observe that the ferroptosis inhibitor, Fer-1, mitigates fibrosis by suppressing ferroptosis. Mechanistically, we unveil that the antioxidant factor NRF2 is activated in response to oxidative stress and mitigates fibroblasts ferroptosis through the SLC7A11/GPX4 signaling axis. In summary, our findings delineate the involvement of fibroblast ferroptosis in arthrofibrosis development, underscoring the potential therapeutic efficacy of inhibiting fibroblast ferroptosis for clinical intervention in arthrofibrosis. • Ferroptosis contributes to fibroblast demise in arthrofibrosis. • Ferroptosis inhibitor, Fer-1, mitigates fibrosis by suppressing ferroptosis. • NRF2 is activated in response to oxidative stress and mitigates fibroblasts ferroptosis through the SLC7A11/GPX4 signaling axis.