Curcumin Alleviates the Osteogenesis Inhibition and the Aging Process in <scp>BMSCs</scp> Induced by Iron Overload Through Activating the <scp>NRF2</scp> / <scp>GPX4</scp> Pathway

Dysregulated proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs) represent a key pathophysiological mechanism in osteoporosis. Recent studies have demonstrated a significant association between ferroptosis and the advancement of osteoporosis, suggesting that targeting ferroptosis could offer novel therapeutic approaches for osteoporosis treatment. Curcumin, a natural antioxidant, has shown therapeutic potential in bone-related disorders; however, its precise mechanisms for modulating BMSC function-particularly via ferroptosis-related pathways-remain poorly characterized. This study investigated whether curcumin alleviates iron overload-induced BMSC dysfunction by targeting ferroptosis, specifically elucidating its molecular mechanisms in promoting osteogenic differentiation and mitigating cellular senescence. Iron-overloaded BMSC in vitro models and in vivo murine systems were established to model osteoporosis-related microenvironments. Curcumin was administered to assess its effects on cellular and systemic outcomes, including bone microstructure, mechanical property, differentiation capacity, senescence markers, iron metabolism, and redox homeostasis by using micro-CT, RNA-seq, RT-qPCR, western blot, immunohistochemical, immunofluorescence, and transmission electron microscope (TEM). Furthermore, Nrf2 siRNA and the Nrf2 inhibitor ML385 were utilized to interrogate curcumin's mechanism of action in iron-overloaded BMSCs. In vivo, curcumin treatment significantly attenuated iron overload-induced bone microstructural damage, mechanical property, and elevated Nrf2 and GPX4 expression in BMSCs. In vitro, curcumin mitigated iron overload-induced ferroptosis in BMSCs by upregulating Nrf2 expression, thereby increasing GPX4 levels. This mechanism consequently delayed cellular senescence and promoted osteogenic differentiation. Our findings establish the Nrf2/GPX4 axis as a critical therapeutic target of curcumin for ameliorating iron overload-induced osteoporosis. This mechanistic insight provides a foundation for developing novel therapeutics against age-related and postmenopausal osteoporosis.