Harmine ameliorates steroid-induced osteonecrosis of the femoral head by modulating metabolism and ferroptosis via HIF1-α

Steroid-induced osteonecrosis of the femoral head (SONFH) often leads to disability in the terminal stage, and there are still no effective drugs for prevention. Harmine (Hm), which is extracted from Peganum harmala L., is a β-carboline alkaloid with a number of biological and pharmacological properties. In this study, we discovered the protective effect of Hm on SONFH in rats. In vitro studies showed that Hm could ameliorate oxidative stress and facilitate osteogenic differentiation in bone mesenchymal stem cells (BMSCs), which play an important role in bone development and repair. Bioinformatics analysis revealed that ferroptosis and the HIF1-α pathway played an important role in SONFH pathogenesis. Mechanistically, Hm treatment alleviated ferroptosis by promoting HIF1-α expression in BMSCs. When shHif1a was used to inhibit HIF1-α expression, the protective effects of Hm disappeared. Meanwhile, we further found that Hm intervention promoted HIF1-α expression to increase GSH production and the GSH/GSSG ratio, which further promoted the scavenging of free radicals. In summary, Hm may be a promising candidate for the treatment of SONFH.