Current research suggests that chronic high-fat dietary intake can lead to bone loss in adults; however, the mechanism by which high-fat diets affect the development of osteoporosis in individuals is unclear. As high-fat diets are strongly associated with ferroptosis, whether ferroptosis mediates high-fat diet-induced bone loss was the focus of our current study. By dividing the mice into a high-fat diet group, a high-fat diet + ferroptosis inhibitor group and a normal chow group, mice in the high-fat group were given a high-fat diet for 12 weeks. The mice in the high-fat diet + ferroptosis inhibitor group were given 1 mg/kg Fer-1 per day intraperitoneally at the start of the high-fat diet. Microscopic CT scans, histological tests, and biochemical indicators of ferroptosis were performed on bone tissue from all three groups at the end of the modelling period. Mc3t3-E1 cells were also used in vitro and divided into three groups: high-fat medium group, high-fat medium+ferroptosis inhibitor group, and control group. After 24 hours of incubation in high-fat medium, Mc3t3-E1 cells were assayed for ferroptosis marker proteins and biochemical parameters, and osteogenesis induction was performed simultaneously. Cellular alkaline phosphatase content and expression of osteogenesis-related proteins were measured at day 7 of osteogenesis induction. The results showed that a high-fat diet led to the development of femoral bone loss in mice and that this process could be inhibited by ferroptosis inhibitors. The high-fat diet mainly affected the number of osteoblasts produced in the bone marrow cavity. The high-fat environment in vitro inhibited osteoblast proliferation and osteogenic differentiation, and significant changes in ferroptosis-related biochemical parameters were observed. These findings have implications for the future clinical treatment of bone loss caused by high-fat diets.Copyright © 2022 RunJiu Zhu et al.