Postmenopausal osteoporosis, characterized by compromised bone density and an increased risk of fractures, is driven by estrogen deficiency and represents a significant clinical challenge. Although previous studies have implicated SIRT5 in mitochondrial metabolism and osteogenesis, its contribution to estrogen deficiency-induced osteoporosis and the role of cuproptosis in this process have remained poorly understood.

In this study published in Genes & Diseases, researchers from Chongqing Medical University, Children’s Hospital of Chongqing Medical University, Chongqing University Cancer Hospital, and the First Affiliated Hospital of Chongqing Medical University identified a previously unrecognized Estrogen–SIRT5–FDX1 regulatory axis that links estrogen signaling to the maintenance of mesenchymal stem cell (MSC) osteogenic potential through modulation of cuproptosis.

Using ovariectomized mouse models, MSCs, molecular analyses, and functional assays, the researchers demonstrated that estrogen deficiency reduced SIRT5 expression, increased copper accumulation in bone tissue, enhanced cuproptosis, and impaired osteogenic differentiation, ultimately resulting in bone loss. Conversely, restoring SIRT5 expression partially rescued the osteogenic capacity of MSCs and attenuated cuproptosis, establishing SIRT5 as a critical regulator of bone homeostasis under estrogen-deficient conditions.

Mechanistically, the study revealed that estrogen promotes SIRT5 expression, enabling SIRT5 to demalonylate ferredoxin 1 (FDX1), a key regulator of cuproptosis. Demalonylated FDX1 undergoes enhanced lysosomal degradation, thereby reducing FDX1 abundance, suppressing cuproptotic signaling, and preserving the osteogenic differentiation of MSCs. Genetic and pharmacological manipulation of SIRT5 and FDX1 confirmed that disruption of this regulatory axis exacerbated cuproptosis and compromised osteogenesis, whereas SIRT5-mediated FDX1 demalonylation effectively restored osteogenic differentiation and suppressed cuproptosis.

Collectively, this study identifies the Estrogen–SIRT5–FDX1 axis as a previously unrecognized molecular mechanism linking estrogen signaling, protein demalonylation, and cuproptosis to the regulation of MSC fate and bone homeostasis. By establishing SIRT5-mediated FDX1 demalonylation as a key mechanism underlying the pro-osteogenic effects of estrogen, the findings highlight SIRT5 as a promising therapeutic target for postmenopausal osteoporosis. Although further validation in human tissues and clinical studies is required, this work provides new mechanistic insights into osteoporosis pathogenesis and lays the foundation for the development of targeted therapies that preserve bone formation by modulating cuproptosis.

Reference

Title of the original paper: SIRT5 mediates the pro-osteogenic effects of estrogen through FDX1 demalonylation and cuproptosis inhibition in mesenchymal stem cells
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102145

Funding Information:
Chongqing Medical University Program for Youth Innovation in Future Medicine (China) (No. W0154)
Chongqing Science and Technology Bureau (China) (No. CSTB2024NSCQ-MSX0411)

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