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Yu Xu, Wencan Zhang, Wenpeng Xu, Shangzhi Li, Dingxin Zhang, Xiangyu Lin, Jincheng Liu, Qingyang Fu, Peijie H, Haipeng Si. Menaquinone-7 alleviates mitochondrial dysfunction and senescence in senile osteoporosis by targeting the PINK1-mediated mitophagy via PXR/ERK/CREB signaling pathway[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101432
Citation: Yu Xu, Wencan Zhang, Wenpeng Xu, Shangzhi Li, Dingxin Zhang, Xiangyu Lin, Jincheng Liu, Qingyang Fu, Peijie H, Haipeng Si. Menaquinone-7 alleviates mitochondrial dysfunction and senescence in senile osteoporosis by targeting the PINK1-mediated mitophagy via PXR/ERK/CREB signaling pathway[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101432

Menaquinone-7 alleviates mitochondrial dysfunction and senescence in senile osteoporosis by targeting the PINK1-mediated mitophagy via PXR/ERK/CREB signaling pathway

doi: 10.1016/j.jpha.2025.101432
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This work was supported by grants from Natural Science Foundation of Shandong Province (No. ZR2023MH050 to H.S., and ZR2023QH219 to P.H.), Qingdao Natural Science Foundation (No. 23-2-1-179-zyyd-jch to H.S.), Qilu Hospital of Shandong University (Qingdao) (No. QDKY2022BS02 to P.H.), Shandong Provincial Medical and Health Science and Technology Project (No. 202304070922 to S.L.) and Qingdao Medical and Health Science and Technology Project (No. 2024-WJKY149 to S.L.).

  • Received Date: Mar. 18, 2025
  • Accepted Date: Aug. 09, 2025
  • Rev Recd Date: Jun. 30, 2025
  • Available Online: Aug. 11, 2025
  • Current therapeutic strategies for senile osteoporosis inadequately address its low-turnover pathology driven by mitochondrial dysfunction and cellular senescence. This study identifies menaquinone-7 (MK-7), a vitamin K2 isoform, as a novel therapeutic agent targeting mitochondrial homeostasis in senile osteoporosis. Through RNA sequencing analysis and intramedullary adeno-associated virus (AAV)-based gene manipulation in aged mice, cellular communication network factor 2 (Ccn2) was identified as a critical mediator of MK-7’s bone-protective effects. Biochemical and proteomic assays revealed that MK-7 binds to the nuclear receptor pregnane X receptor (PXR), activating the extracellular signal-regulated kinases 1/2 (ERK1/2)/cyclic AMP-responsive element-binding protein (CREB) signaling cascade to upregulate Ccn2 in senescent bone marrow mesenchymal stem cells (BMSCs). This pathway enhanced PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy, reducing mitochondrial DNA damage, reactive oxygen species (mtROS), and senescence-associated secretory phenotype (SASP), while restoring metabolic function. MK-7 redirected BMSC differentiation from adipogenic to osteogenic lineages, effectively mitigating age-related bone loss in vivo. Mechanistically, MK-7 stabilized PXR via direct interaction at the F285 residue, as confirmed by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular docking. PXR activation further promoted ERK1/2/CREB-dependent Ccn2 expression, which orchestrated mitochondrial quality control and cellular energy metabolism. Our findings establish MK-7 as a dual-function agent that concurrently alleviates senescence and metabolic imbalance in bone tissue, offering a safe and targeted strategy for senile osteoporosis. This study provides critical insights into the pharmacological modulation of mitochondrial pathways and highlights MK-7’s translational potential in geriatric bone health.
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