Current insights into the functional roles of ferroptosis in musculoskeletal diseases and therapeutic implications

Abstract

Ferroptosis is a novel type of cell death associated with iron accumulation and excessive lipid peroxidation. Elucidating the underlying molecular mechanisms of ferroptosis is intensively related to the development and treatment of multiple diseases, including musculoskeletal disorders. Moreover, in vitro and in vivo studies have shown the importance of oxidative stress in musculoskeletal conditions such as osteoporosis, osteoarthritis, rheumatoid arthritis, and osteosarcoma. Ferroptosis-derived clinical management of musculoskeletal diseases offers tremendous and attractive opportunities. Notably, ferroptosis agonists have been proven to enhance the sensitivity of osteosarcoma cells to conventional therapeutic strategies. In this review, we have mainly focused on the implications of ferroptosis regulation in the pathophysiology and therapeutic response of musculoskeletal disorders. Understanding roles of ferroptosis for controlling musculoskeletal diseases might provide directions for ferroptosis-driven therapies, which could be promising for the development of novel therapeutic strategies.

Targeting Ferroptosis in Bone-Related Diseases: Facts and Perspectives

“…Some progress has been made in the application of ferroptosis inhibitors or inducers, ferroptosis inhibitors such as FSP-1, Fer-1, and DFO have shown therapeutic potential in bone-related diseases, but most of these studies remain in animal or in vitro experiments, and relevant clinical studies are still lacking. 118 , 138 , 176 Because different cells (OBs, OCs, BMSCs, chondrocytes, FLSs, OS cells) have different tolerance to ferroptosis, ferroptosis is a double-edged sword in bone-related diseases. Clinical studies are needed to explore how to use ferroptosis inducers or inhibitors in specific bone-related diseases.…”

Ferroptosis-Related Molecular Clusters and Diagnostic Model in Rheumatoid Arthritis

“…As typical systemic autoimmune diseases, neutropenia is associated with neutrophil ferroptosis in patients with systemic lupus erythematosus, whereas peripheral neutrophil numbers are higher in patients with RA than in HCs, which implies a different pathogenesis [ 25 ]. In RA patients, we have paid more attention to the relationship between ferroptosis and synovium, especially SFs [ 26 ]. In addition, RA patients are known to have an increased risk of cardiovascular disease, and recent evidence suggests that ferroptosis may contribute to this heightened risk [ 27 , 28 ].…”