6‐Shogaol Promotes Fatty Acid Oxidation and Osteogenic Differentiation in Aged Bone Marrow Mesenchymal Stem Cells Through Allosteric Regulation of Carnitine Palmitoyltransferase 1A

ABSTRACT Age‐related osteoporosis is heavily driven by the senescent decline of bone marrow mesenchymal stem cells (BMSCs), characterized by impaired osteogenic differentiation and excessive lipid accumulation. Defective fatty acid oxidation (FAO) is a critical metabolic hallmark of this pathogenic shift. This study aimed to investigate whether 6‐Shogaol (6S), a bioactive dietary compound, could rescue the osteogenic potential of senescent BMSCs by remodeling lipid metabolism. The effects of 6S were evaluated in vitro using replicative and D‐galactose‐induced senescent BMSC models, and in vivo using 18‐month‐old naturally aged mice. Underlying mechanisms were elucidated through transcriptomic and metabolomic analyses, oxygen consumption rate (OCR) measurements, molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) assays. 6S treatment effectively alleviated the senescence phenotype, reduced lipid droplet accumulation, and restored osteogenic differentiation in aged BMSCs. In vivo administration of 6S significantly attenuated bone loss and improved trabecular microarchitecture in aged mice. Mechanistically, multi‐omics and metabolic flux analyses revealed that 6S promoted FAO by enhancing the enzymatic activity of CPT1A via direct binding to the GLN30 residue. This binding allosterically increases the spatial distance between GLN30 and GLU3, thereby antagonizing the physiological inhibition of CPT1A by Malonyl‐CoA (MCoA). Mutation of the GLN30 residue (Q30A) abolished the 6S‐mediated restoration of FAO and osteogenic capacity. 6‐Shogaol acts as a novel allosteric modulator of CPT1A. By specifically targeting the GLN30 residue to relieve Malonyl‐CoA inhibition, 6S restores FAO homeostasis in senescent BMSCs and promotes osteogenesis, highlighting a promising metabolic intervention strategy for age‐related osteoporosis.