Hyperoside prevents osteoporosis by activating the PI3K/AKT signaling pathway to inhibit oxidative stress and promote osteogenesis

Hyperoside (Hyp), a naturally occurring flavonol glycoside derived from <i>Crataegus</i>, otherwise known as hawthorn, possesses potent antioxidant properties and has demonstrated therapeutic potential in various oxidative stress‑related diseases, including osteoporosis (OP). However, the precise molecular mechanisms underlying the anti‑osteoporotic effects of Hyp remain to be fully elucidated. The present study aimed to evaluate the therapeutic efficacy of Hyp against OP and to elucidate its underlying mechanisms. An osteoporotic mouse model was established via bilateral ovariectomy (OVX) to assess the <i>in vivo</i> efficacy of Hyp. Network pharmacology was employed to predict the potential therapeutic targets of Hyp in OP. In vitro experiments using bone marrow mesenchymal stem cells (BMSCs) were performed to validate the findings. Techniques including alkaline phosphatase staining, Alizarin red S staining, reverse transcription‑quantitative PCR and western blotting were used to assess osteogenic differentiation and molecular signaling pathways. Micro‑CT analysis revealed that Hyp significantly ameliorated OVX‑induced bone loss in mice. Network pharmacology identified the PI3K/AKT signaling pathway as a potential key target. <i>In vitro</i>, Hyp significantly reduced H2O2‑induced oxidative stress in BMSCs and promoted their osteogenic differentiation. Mechanistically, Hyp was found to activate the PI3K/AKT signaling pathway, suggesting its notable role in mediating the antioxidant and osteoinductive effects of Hyp. Summarily, Hyp may effectively alleviate OVX‑induced OP in mice, potentially by mitigating oxidative stress and promoting osteogenesis via activation of the PI3K/AKT signaling pathway. These findings provide novel insights into the therapeutic mechanism of Hyp and support its potential as a candidate agent for OP treatment.