Baicalein Ameliorates Postmenopausal Osteoporosis With Iron Accumulation by Inhibiting Osteoclastogenesis via Nrf2 Activation

ABSTRACT Postmenopausal osteoporosis (PMOP) is frequently complicated by iron accumulation, which exacerbates bone loss. Baicalein, a natural flavonoid with iron‐chelating and antioxidant properties, has shown bone‐protective effects, but its role in iron‐overloaded PMOP remains unclear. This study investigated whether baicalein ameliorates iron‐accumulated PMOP by inhibiting osteoclastogenesis via Nrf2 activation. In vitro, bone marrow‐derived macrophages (BMMs) were induced into osteoclasts with RANKL under iron overload. Baicalein (10 μM) suppressed osteoclast differentiation, F‐actin ring formation, and bone resorption, reduced intracellular and mitochondrial ROS, lowered Fe 2+ and total iron content, and upregulated Nrf2 nuclear translocation and HO‐1 expression. These effects were abrogated by the Nrf2 inhibitor ML385 or Nrf2 siRNA. In vivo, an ovariectomized (OVX) mouse model with iron dextran injection (100 mg/kg/week) was used. Oral baicalein treatment (100 mg/kg/day) significantly prevented bone loss, improved bone microarchitecture and biomechanical properties, reduced iron deposition in bone, liver and spleen, lowered serum ferritin and bone ROS, and activated Nrf2 signaling in bone tissue. Co‐administration of ML385 reversed these protective effects. Collectively, baicalein ameliorates iron‐accumulated postmenopausal osteoporosis by activating the Nrf2 pathway, thereby inhibiting osteoclast differentiation and bone resorption. Baicalein represents a promising multi‐target candidate for treating PMOP, especially in patients with concomitant iron accumulation.