A food-derived bioactive small molecule DRL-7 enhances bone marrow stem cell function via CXCL12-CXCR4–PI3K-Akt signaling

Diet-derived bioactive compounds play a crucial role in maintaining skeletal health, yet their cellular and molecular mechanisms remain incompletely understood. Bone marrow mesenchymal stem cells (BMSCs) are key regulators of bone homeostasis, and their functional decline contributes to age- and menopause-associated bone loss. Here, we identify DRL-7, a food-derived bioactive small molecule, as a potent regulator of BMSC function and bone microenvironment homeostasis. Using integrated in vivo, in vitro, and multi-omics approaches, we demonstrate that DRL-7 enhances BMSC proliferation, migration, and osteogenic differentiation, accompanied by significant improvement in trabecular microarchitecture and bone mineral density in ovariectomized models. Mechanistically, DRL-7 promotes translocation of the chemokine receptor CXCR4 to the plasma membrane, thereby activating CXCL12/CXCR4–PI3K/Akt signaling. Activation of this pathway supports osteogenic gene expression and extracellular matrix formation while simultaneously improving mitochondrial energy metabolism and glutathione-dependent antioxidant capacity. These metabolic adaptations reduce oxidative stress and provide a favorable intracellular environment for sustained stem cell activity. Importantly, inhibition of CXCR4 or PI3K abolishes the beneficial effects of DRL-7 on BMSC function, confirming pathway dependence. Collectively, our findings reveal a previously unrecognized mechanism by which a food-derived bioactive molecule coordinates chemokine signaling and metabolic regulation to preserve stem cell function and skeletal integrity in preclinical models. This study provides mechanistic evidence supporting the potential application of DRL-7-like food bioactives in nutritional strategies for bone health maintenance. However, given the limitations of rodent models, further clinical validation is essential to determine their efficacy and safety in human postmenopausal osteoporosis management.