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

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 K 2 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. • MK-7 targets PXR to activate ERK/CREB-Ccn2 axis, restoring mitophagy in senile osteoporosis. • MK-7 binds PXR at F285 residue, validated by DARTS, CETSA, and molecular docking. • Dual action: MK-7 mitigates senescence and metabolic dysfunction in aged BMSCs. • Ccn2-driven mitophagy reduces mtDNA damage and SASP, reversing bone loss. • MK-7 offers a safe strategy for geriatric bone health via mitochondrial quality control.