Chikusetsusaponin IVa improves osseointegration by inhibiting osteoblast ferroptosis via the GSK3β/NRF2/GPX4 pathway

Osteoporosis-induced implant loosening can lead to surgical failure and impede patient recovery. Various approaches, including anti-osteoporosis drugs, have been explored to improve implant stability, however, they fail to improve bone formation or restore bone balance, underscoring the need for novel therapeutic strategies. Certain natural products, such as Chikusetsusaponin IVa (CHSs IVa) exhibit strong antioxidant and bone-protective properties, making them viable options for improving implant stability. This study aims to investigate the inhibitory effect of CHS IVa on ferroptosis and its potential to restore bone formation in bone marrow mesenchymal stem cells (BMSCs) and mouse embryonic osteoblast precursor cells (MC3T3-E1). By mitigating ferroptosis, CHS IVa increases bone mass and promotes bone integration, improving implant stability. Using a rat model of implant loosening under osteoporosis, we conducted morphological analysis, bone microstructure assessment, on tissue surrounding the implants. In vitro experiments and phosphorylated antibody chip experiments combined with molecular docking were employed to investigate the inhibitory mechanism of CHS IVa. Our findings reveal that ferroptosis occurs around internal implants under osteoporotic conditions. CHS IVa inhibits ferroptosis in osteoblasts by intervening in the GSK3β/NRF2/GPX4 pathway, saving osteoblasts osteogenic ability and increasing bone mass at the implant bone interface, further enhancing implant stability.