Liquiritin targets NF-κB/MAPK signaling to attenuate osteoclastogenesis and triggers apoptosis through PPARγ activation.

BACKGROUND

Postmenopausal Osteoporosis (PMOP) is an estrogen-deficiency disorder that leads to impaired bone remodeling and a higher incidence of fractures. Liquiritin, a flavonoid from Glycyrrhiza uralensis, has documented bioactivities but previously unexplored potential for PMOP treatment.

PURPOSE: To investigate liquiritin's therapeutic effects on PMOP and its underlying mechanisms, constituting the first comprehensive investigation of its role in osteoclasts regulation and apoptosis induction within PMOP pathophysiology.

METHODS

Network pharmacology was employed to predict potential targets of Liquiritin in PMOP. The CCK-8 assay assessed its effect on bone marrow-derived macrophages (BMDMs) viability. RANKL was used to induce BMDMs differentiation into mature osteoclasts. TRAcP and F-actin staining detected osteoclasts formation; bone resorption assays evaluated functionality. Western blotting and immunofluorescence were applied to evaluate osteoclasts-related proteins, MAPK/NF-κB pathway activity, and apoptosis. Notably, molecular docking predicted Liquiritin's binding to PPARγ, validated by CETSA. An OVX-induced PMOP mouse model was constructed in vivo; bone microarchitecture and osteoclasts activity were evaluated using micro-CT, H&E, and TRAcP staining.

RESULTS

Liquiritin suppressed osteoclasts formation and bone resorption in vitroand mitigated bone loss in vivo by downregulating osteoclasts-specific genes, inhibiting MAPK/NF-κB pathways, and most importantly, inducing PPARγ-mediated apoptosis-a novel mechanistic insight not previously reported.

CONCLUSION

Liquiritin exerts anti-osteoporotic effects by targeting Osteoclastogenesis, inducing apoptosis, and inhibiting bone resorption via PPARγ activation, highlighting its novel therapeutic potential for PMOP treatment.