Abstract
Osteocytes, the most abundant bone cells, are central regulators of bone remodeling that also exert endocrine control over systemic metabolism. Among the factors they produce, Lipocalin-2 (LCN2) has emerged as a cytokine linking bone and energy homeostasis, yet its local role within the skeleton remains elusive. Here, we identify that LCN2 promotes intracellular iron accumulation, mitochondrial dysfunction, and lipid peroxidation through its receptor SLC22A17, and drives ferroptotic cell death. Dmp1-Cre–mediated deletion of Lcn2 preserves mitochondrial integrity, reduces intracellular iron and lipid peroxidation, and enhances osteocyte dendricity and lacunocanalicular connectivity. Mechanistically, loss of Lcn2 suppresses Wnt antagonists DKK1 and SOST, thereby promoting Wnt/β-catenin signaling and stimulating osteoblast-mediated bone formation. Notably, Dmp1-Cre-mediated deletion of Lcn2 does not alter systemic energy balance, underscoring LCN2’s local skeletal function. These findings define the LCN2–SLC22A17 axis as a local regulator of osteocyte ferroptosis, Wnt/β-catenin signaling, and skeletal fragility.
Data availability
All data and materials are included in this manuscript. Reagents associated with this study are available from the corresponding author upon request. RNA-seq data generated in this study have been deposited in the SRA database under accession code BioProject PRJNA1249006.
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Acknowledgements
This research was supported by NIH-NIDDK K01 DK129404 (NSD), Arkansas Biosciences Institute AWD55316 (NSD), NIH-NIGMS 1P20GM125503 (NSD), USDA-ARS 6026-10700-001-000D (NSD, UW), NIH-NIGMS P20GM109096 (UW), DoD Award HT9425-24-1-0039 (NSD), NIH-KL2 TR003108 (AYS), and NIH-NCATS UL1TR003107 (AYS). The authors would like to thank Drs. Teresita Bellido, Jesús Delgado-Calle, Charles O’Brien, and Maria Almeida for constructive suggestions.
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VK and NSD conceived and designed the research. VK, MC, and FM collected specimen samples. VK, MC, FM, JC, YZ, CGS, AYS, RMA, UDW, and NSD analyzed data. VK and NSD provided data interpretation, made figures and tables. VK and NSD wrote, reviewed, and revised the manuscript. NSD procured funding, provided project leadership, and supervision. All authors reviewed and approved the manuscript for publication.
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All animal studies were approved by the Institutional Animal Care and Use Committee of the University of Arkansas for Medical Sciences (IPROTO202200000381) and conducted in accordance with institutional guidelines. All reagents and experiments conducted in this study are compliant with the institutional biological safety committee (SPROTO202200000081) of the University of Arkansas for Medical Sciences.
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Khanal, V., Carroll, M., Moradi, F. et al. Osteocytic Lipocalin-2 regulates bone formation locally through iron-dependent ferroptosis and Wnt suppression. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02956-9
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DOI: https://doi.org/10.1038/s41420-026-02956-9
