Sofalcone inhibits osteoclastogenesis through Keap1/Nrf2 signaling activation and mitigates ovariectomy-induced bone loss.

Osteoporosis, a metabolic bone disorder, predominantly affects postmenopausal women and frequently results in pathological fractures. Current treatments for this condition often entail significant side effects, limiting their clinical utility. Sofalcone (SFC), a phenolic derivative isolated from the Chinese herb Sophora tonkinensis, has demonstrated antioxidative, anti-inflammatory, and anti-ulcer capabilities, has been less studied for its effects on osteoclasts and osteoporosis. Our in vitro studies reveal that SFC inhibits osteoclastogenesis and reduces osteoclastic bone resorption. It achieves this by enhancing the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which boosts the expression of antioxidant genes, decreases the production of reactive oxygen species (ROS), and suppresses activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Further investigations using ovariectomized (OVX) mice have shown that SFC mitigates bone density loss and improves bone microarchitecture, suggesting its utility as both a preventive and therapeutic measure against osteoporosis.