Forsythiaside A Suppresses Ferroptosis and Mitigates Type 2 Diabetes Osteoporosis Through the NRF2/GPX4 Axis

ABSTRACT Type 2 diabetes osteoporosis (T2DOP) is a chronic bone metabolic disorder that has led to substantial economic losses worldwide. Unlike conventional postmenopausal osteoporosis, the hyperglycemic microenvironment in T2DOP significantly heightens the risk of fractures and osteonecrosis. However, effective pharmacological interventions for T2DOP remain scarce. Research indicates that ferroptosis is crucial in the development of T2DOP. Forsythiaside A (FA), extracted from Forsythia suspensa fruit, demonstrates various biological activities such as anti‐inflammatory, antioxidant, neuroprotective effects, and ferroptosis inhibition. This study aims to investigate the effects and mechanisms of FA in the context of T2DOP. We developed T2DOP models both in vitro and in vivo and subsequently treated them with FA. The results demonstrated that FA effectively inhibited ferroptosis and mitigated T2DOP. Mechanistic studies indicate that FA may promote the nuclear translocation of nuclear factor erythroid 2‐related factor 2 (Nrf2), enhancing glutathione peroxidase 4 (GPX4) expression to inhibit ferroptosis. FA concurrently boosts the expression of proteins associated with osteogenesis. In conclusion, our study highlights FA as a potential therapeutic agent for the treatment of T2DOP.