4,4′-Dimethoxychalcone ameliorates estrogen-deficient osteoporosis by targeting PTP1B to inhibit the c-Src/NFATc1 signaling axis

Postmenopausal osteoporosis (PMOP) is a skeletal disease linked to immune dysregulation, characterized by the overactivation of myeloid-lineage osteoclasts. To address the limitations of current therapies, this study investigated the immunomodulatory potential and molecular mechanism of the natural flavonoid 4,4′-dimethoxychalcone (DMC). Using in vitro and in vivo models, we found that DMC exhibited a desirable dual-action profile, potently inhibiting osteoclast differentiation while also promoting osteogenesis. Mechanistically, we identified Protein Tyrosine Phosphatase 1B (PTP1B) as a novel, direct target of DMC. We demonstrated that DMC inhibits PTP1B activity, preventing Proto-oncogene tyrosine-protein kinase Src (c-Src) activation and thereby blocking the downstream calcium/ Nuclear Factor of Activated T-cells, cytoplasmic 1 (NFATc1) signaling cascade essential for osteoclastogenesis; an effect that was reversed by PTP1B knockdown. In vivo, DMC administration rescued bone loss and restored bone strength in an ovariectomy (OVX) mouse model. In conclusion, this work establishes DMC as a potent immunomodulatory agent for treating osteoporosis and validates PTP1B as a new pharmacological target within the osteoimmune system. • DMC acts as a dual agent: inhibiting osteoclast activity while promoting osteogenesis. • This study provides the first pharmacological proof-of-concept for targeting PTP1B to treat osteoporosis. • DMC directly inhibits PTP1B to suppress the c-Src/NFATc1 signaling axis in osteoclasts. • DMC rescues bone loss, restores bone homeostasis, and improves bone strength in OVX mice.