Curcumin attenuates hindlimb unloading-induced bone loss by suppressing NF-κB-mediated osteoclast activation

Microgravity exposure or mechanical unloading profoundly disrupts skeletal homeostasis, leading to rapid bone loss that poses a major challenge during spaceflight and long-term bed rest. Despite existing countermeasures, effective pharmacological strategies with minimal side effects remain elusive. Here, we identify curcumin, a naturally polyphenolic compound with pleiotropic bioactivity, as a promising candidate unloading-induced osteoporosis. Daily administration of curcumin (200 mg/kg) markedly mitigates the reduction of trabecular bone mass and microarchitecture under hindlimb unloading (HU) mouse model, as evidenced by increased BV/TV, Tb.N, and Tb.Th, and reduced Tb.Sp. Curcumin significantly suppressed osteoclast function and bone resorption, reducing TRAP⁺ multinucleated cells and downregulating Ctsk, Mmp9, Trap, Nfatc1, and NFAT2 expression, while exerted minimal influence on cortical bone strength or key osteogenic markers (Alp, Col1a1, Bglap). Mechanistically, curcumin inhibited the NF-κB signaling cascade, specifically through attenuated phosphorylation of p65 and IκBα, which restrained osteoclastogenesis. Collectively, these findings demonstrated the potential roel of curcumin in preventing microgravity- or disuse-related bone loss.