Baicalein Attenuates Disuse-Driven Skeletal Senescence in Association with Gut Microbiota Modulation

The progression of skeletal senescence under mechanical unloading conditions elevates fracture risk, emerging as a critical health challenge for the general population and astronauts during spaceflight. Nevertheless, current therapeutic strategies demonstrate persistent limitations in efficacy and safety, with unresolved challenges in long-term sustainability. Baicalein, a natural flavonoid compound, exhibits favorable anti-aging and anti-inflammatory effects, while its therapeutic potential and underlying mechanism in bone disorders remain unknown. In this study, a hind limb unloading (HLU) rat model was employed as a disuse simulation, after which the HLU rats received baicalein treatment by gavage at 30 mg·kg^-1·day^-1 for 4 weeks. Our results show that baicalein mitigates disuse-driven skeletal aging by ameliorating trabecular microstructure (Tb. N increased by 38.04%), accelerating bone mineral apposition rate (MAR increased by 42.76%), increasing bone mineral density (1.20-fold vs. model group), improving biomechanical strength (ultimate load +31.64%) and downregulating senescence-associated markers p16, p21, p53 in tibial tissue. Additionally, baicalein alleviated the unloading-induced high bone turnover, as evidenced by reducing serum levels of both osteogenic biomarkers ALP, PINP, BGP and osteoclastic biomarkers TRACP 5b, RANKL, NTX. Moreover, baicalein suppressed the inflammatory response caused by mechanical unloading, attributed to the restriction of pro-inflammatory factors TNF-α, IL-6, IL-8, IFN-γ and the promotion of anti-inflammatory cytokines IL-4, IL-10. Importantly, baicalein ameliorated the unloading-induced gut microbiota disorder through the diminished abundance of Proteobacteria and elevated abundance of Actinobacteria and Firmicutes, which were negatively associated with inflammatory response. Overall, our study provides evidence that baicalein inhibits the inflammatory response through the regulation of gut microbiota balance, which plays a role in preserving bone homeostasis.