Naringenin ameliorates postmenopausal osteoporosis by inhibiting BMSC oxidative stress via the PI3K/AKT/NRF2 pathway.

Abstract

Oxidative stress plays a critical role in the pathogenesis of various bone diseases, particularly osteoporosis. Naringenin, a small molecule compound confirmed to possess antioxidative stress properties, exerts anti-inflammatory effects in multiple diseases and can ameliorate osteoporotic symptoms. However, the precise mechanism by which Naringenin treats osteoporosis remains unclear. This study investigates the mechanism by which Naringenin inhibits oxidative stress in Bone Marrow Mesenchymal Stem Cells (BMSCs) to treat postmenopausal osteoporosis (PMOP). A mouse model of postmenopausal osteoporosis (PMOP) was established by ovariectomy (OVX). Micro-computed tomography (micro-CT) and histological staining were used to evaluate the therapeutic efficacy of naringenin against PMOP. Network pharmacology and molecular docking were applied to explore the underlying mechanism of naringenin in the treatment of PMOP. Cell counting kit-8 (CCK-8) assay, alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, Western blot and immunofluorescence staining were performed to investigate the effects and mechanisms of naringenin on relieving oxidative stress in bone marrow mesenchymal stem cells (BMSCs) and ameliorating PMOP. Naringenin alleviated bone loss caused by postmenopausal osteoporosis and upregulated the expression of BCL-2, RUNX2 and NRF2 in BMSCs within bone tissues. In the hydrogen peroxide (H2O2)-induced BMSC injury model, naringenin activated the PI3K/AKT/NRF2 signaling pathway, thereby inhibiting oxidative stress-mediated cell apoptosis and the decline in osteogenic differentiation capacity. Treatment with a PI3K/AKT inhibitor reversed these beneficial effects, confirming the specificity of this signaling pathway. Naringenin treats postmenopausal osteoporosis by inhibiting BMSC oxidative stress via the PI3K/AKT/NRF2 pathway, presenting a potential new target for osteoporosis therapy.

Key Findings

• Naringenin alleviates bone loss in a mouse model of postmenopausal osteoporosis by upregulating BCL-2, RUNX2, and NRF2 expression in bone marrow mesenchymal stem cells (BMSCs).
• Naringenin activates the PI3K/AKT/NRF2 signaling pathway in H2O2-induced BMSC injury, reducing oxidative stress-mediated apoptosis and improving osteogenic differentiation capacity.
• Inhibition of the PI3K/AKT pathway reverses the protective effects of naringenin, confirming the pathway's role in mediating its antioxidative and osteoprotective actions.

Clinical Significance

Citation

Zhang Yalong, Cao Shuyan, Li Dailuoet al.. Naringenin ameliorates postmenopausal osteoporosis by inhibiting BMSC oxidative stress via the PI3K/AKT/NRF2 pathway. Naunyn-Schmiedeberg's archives of pharmacology. 2026-Jun-19.