SIRT5 mediates the pro-osteogenic effects of estrogen through FDX1 demalonylation and cuproptosis inhibition in mesenchymal stem cells.

Osteoporosis, a common orthopedic disease predominantly caused by estrogen deficiency in postmenopausal women, continues to pose a significant public health challenge due to the poorly understood molecular mechanisms. While cuproptosis has been implicated in various pathological conditions, its concrete role in the pathogenesis of osteoporosis remains unknown. Equally ambiguous remains the functional role of Sirtuin 5 (SIRT5), a mitochondrial deacylase with well-characterized involvement in aging and bone formation, in estrogen deficiency-associated osteoporosis. In the present study, we identified a novel potential Estrogen/SIRT5/Ferredoxin 1 regulatory axis that modulates both cuproptosis and the lineage commitment of mesenchymal stem cells. Using an ovariectomized mouse model, we observed that serum copper levels were reduced, whereas copper accumulation was elevated in bone tissue. Estrogen deficiency down-regulated SIRT5 expression, promoted cuproptosis, and induced obvious bone loss. Cuproptosis directly impaired the osteogenic differentiation in mesenchymal stem cells, while SIRT5 overexpression partially rescued this lineage commitment defect. Mechanistically, we showed that estrogen up-regulated SIRT5 expression, which in turn mediated Ferredoxin 1 demalonylation and enhanced its lysosomal degradation. This dual regulatory mechanism may effectively suppress cuproptosis and restore the osteogenic potential of mesenchymal stem cells. Our findings suggest that the novel Estrogen/SIRT5/FDX1 axis may function as a key regulator of bone homeostasis, and identify SIRT5 as a potential therapeutic candidate for postmenopausal osteoporosis, likely through its capacity to reduce the cuproptosis-like features of mesenchymal stem cells.