Antioxidant dipeptide, cyclo (Phe-Phe), protects against bone dysplasia by suppression of phospholipid peroxidation

Prenatal exposure to dexamethasone (Dex) has been identified as a significant factor that impairs longitudinal skeletal growth in fetuses, resulting in notable deficiencies in bone development. However, effective treatment options are currently limited due to the lack of understanding of the underlying mechanisms. This study indicates that phospholipid peroxidation and ferroptosis contribute to Dex-induced fetal bone dysplasia, as demonstrated through chick embryo and zebrafish larvae models. Furthermore, the antioxidative dipeptide cyclo(Phe-Phe) (CPP), found in various protein hydrolysates, was shown to alleviate bone dysplasia caused by Dex or phospholipid peroxidation. Mechanistically, CPP inhibits phospholipid peroxidation and ferroptosis by enhancing the transcription of glutathione peroxidase 4 (GPX4). These findings establish CPP as a key antioxidant peptide in protein hydrolysates, elucidate the harmful effects of phospholipid peroxidation and ferroptosis in prenatal Dex-induced bone development defects, and suggest CPP as a promising peptide-based therapeutic approach for the treatment of bone dysplasia. • The bone dysplasia caused by dexamethasone exposure involves phospholipid peroxidation and ferroptosis. • The dipeptide cyclo (Phe-Phe) effectively reverses inhibition of bone development induced by dexamethasone. • Cyclo (Phe-Phe) restrains phospholipid peroxidation by upregulating the expression of GPX4.