Objective To investigate the protective effects of naringenin(NRG)against dexamethasone(DEX)-induced osteoporosis(OP)in rats. Methods Molecular docking of NRG was done with AutoDock Vina 1.2.0 software.Forty-eight female Wistar rats were randomly divided into six groups(n=8 each):normal control(NC),DEX(7 mg/kg,i.m.),NRG-low(NRG-L;25 mg/kg,i.g.),NRG-medium(NRG-M;50 mg/kg,i.g.),NRG-high(NRG-H;100 mg/kg,i.g.),and alendronate(ALN;0.25 mg/d,i.g.)groups.OP was induced by administering DEX once a week for five weeks in all groups except NC group.Begining in the third week after the initial DEX administration,the rats in NRG-L,NRG-M,NRG-H,and ALN groups received the corresponding treatments daily for three weeks,while NC and DEX groups received no additional treatment.Serum samples were collected at the end of the experiment for biochemical,bone turnover,antioxidant,lipid profile,and inflam-matory cytokine analyses.Femur bones underwent physical parameter testing and histopathological examination. Results The molecular docking results illustrated that NRG docked with calcitonin(CT),low-density lipoprotein(LDL),bone morphogenetic protein(BMP),vascular endothelial growth factor(VEGF)receptor,forkhead transcription factors,and osteoprogenitor cells showed good binding energy.In rats administered with 25,50,and 100 mg/kg NRG,there was a signif-icant enhancement in serum biochemical indices,characterized by a reduction in tartrate-re-sistant acid phosphatase(TRAP),parathyroid hormone(PTH),and an elevation in osteocal-cin(OC)and CT levels(P<0.05,P<0.01,and P<0.001,respectively).Despite no significant changes in thickness,weight,and length(P>0.05),there was a marked increase in bone min-eral density(BMD)(P<0.01,P<0.001,and P<0.001,respectively).Antioxidant enzyme markers showed significant upregulation,with higher glutathione,superoxide dismutase,and catalase,and a concurrent decrease in malondialdehyde(MDA)(P<0.05,P<0.01,and P<0.001,respectively).The lipid profile also improved significantly,with lower cholesterol(CH),triglycerides(TG),and low-density lipoprotein(LDL)levels,and an increase in high-density lipoprotein(HDL)level(P<0.05,P<0.01,and P<0.001,respectively).Inflammatory cy-tokine levels were reduced,as evidenced by decreases in tumor necrosis factor(TNF),inter-leukin(IL)-6,and IL-1β(P<0.05,P<0.01,and P<0.001,respectively).Furthermore,histolog-ical alterations revealed obvious improvements,and the body weight of rats treated with NRG showed an increase compared with DEX group. Conclusion These findings imply that NRG exhibited a protective effect against DEX-in-duced OP in rats as it promotes the bone formation process by increasing the number of bone turnover markers including OC and CT,and restoring of antioxidant status,lipid metabolism,and inflammatory markers.