γ-Mangostin attenuates osteoclastogenesis and bone resorption by suppressing the PI3K/AKT/NF-κB pathway.

Background: Postmenopausal osteoporosis (PMOP), driven predominantly by estrogen deficiency-induced hyperactivation of osteoclasts, represents a critical public health burden. The pursuit of naturally sourced inhibitors of osteoclast function with minimized adverse effects remains a pivotal research endeavor. γ-Mangostin (γ-Mag), a natural xanthone derived from the pericarp of mangosteen, possesses broad anti-inflammatory and anti-tumor activities. Nevertheless, its influence on bone metabolic homeostasis, particularly osteoclast biology, remains entirely unexplored. This study aims to elucidate the impact of γ-Mag on osteoclast differentiation and function, and to evaluate its therapeutic potential for PMOP. Methods: Primary rat bone marrow-derived macrophages (BMMs) were isolated and stimulated with RANKL to establish an Results: At non-cytotoxic concentrations (≤4 μM), γ-Mag potently and concentration-dependently suppressed RANKL-induced osteoclast formation, disrupted F-actin ring integrity, and impaired bone resorptive activity. Mechanistically, γ-Mag significantly attenuated the RANKL-triggered activation of the PI3K/AKT/NF-κB signaling axis, as demonstrated by reduced phosphorylation of PI3K, AKT, p65, and IκB. This upstream suppression consequently led to the downregulation of the pivotal transcription factors C-FOS and NFATc1, and inhibited NFATc1 nuclear translocation. Conclusion: Our findings demonstrate that γ-Mag inhibits osteoclastogenesis and bone resorption by targeting the PI3K/AKT/NF-κB pathway, thereby blunting the C-FOS/NFATc1 transcriptional program. This study establishes γ-Mag as a promising natural lead compound for the treatment of postmenopausal osteoporosis.