Iron overload-induced ferroptosis of osteoblasts as a potential therapeutic target for osteoporosis

Osteoporosis is a systemic skeletal disorder marked by reduced bone mass, compromised bone microarchitecture, heightened fragility, and an increased risk of fractures. Fractures resulting from osteoporosis are a leading cause of mortality and disability among the elderly. Ferroptosis is an emerging form of programmed cell death that occurs due to unregulated iron-dependent lipid peroxidation. Our study reveals that high-iron exposure triggers ferroptosis in osteoblasts through the FTH1/FTL pathway, as demonstrated by both in vivo and in vitro experiments. Ferroptotic osteoblasts initiate a co-stimulatory pathway that fosters osteoclast differentiation, culminating in an osteoporotic phenotype in mice. We propose that the high-iron intervention in mice could be utilized as a novel model for replicating clinical osteoporosis, and that inhibiting ferroptosis in osteoblasts may represent a promising therapeutic strategy for the treatment of osteoporosis. Overall, our findings offer fresh perspectives on the pathogenesis of OP and identify potential new targets for the clinical management of this condition.