CoCrMo Particles Drive Macrophage Ferroptosis via Inhibiting the Sirtuin 1/NRF2/GPX4 Pathway to Promote...

Nanoscale wear particles generated over time in the implant-bone interface induce profound periprosthetic inflammatory osteolysis, the most common complication after total joint arthroplasty, while macrophages serve as key initiators of this response. Ferroptosis represents a recently identified mode of regulated cell death distinguished by its nonapoptotic nature and reliance on iron-driven lipid peroxidation, which is strongly linked to inflammatory processes within macrophages. However, the contribution of macrophage ferroptosis to the development of wear particle-induced periprosthetic osteolysis has not yet been elucidated. Here, we revealed the existence of macrophage ferroptosis in both the soft tissue from the implant-bone interface of patients with aseptic loosening and wear-particle-stimulated BMDMs, which promoted inflammatory osteolysis. Our results further suggested that wear particle-induced macrophage ferroptosis is mainly associated with GPX4-related antioxidized function impairment rather than iron metabolism alteration. Mechanistically, we found that wear particle-induced macrophage ferroptosis was mediated by inhibition of the Sirtuin 1/Nrf2/GPX4 pathway, while activation of this pathway effectively alleviates the wear particle-related periprosthetic inflammatory osteolysis. Overall, our results uncovered that wear particles drive macrophage ferroptosis via inhibiting the Sirtuin 1/NRF2/GPX4 pathway to induce periprosthetic inflammatory osteolysis and provide new insights into the intricate cellular and molecular mechanisms responsible for aseptic implant loosening.