Modulation of Arachidonic Acid Metabolism by Pinoresinol Diglucoside Ameliorates Osteogenic Dysfunction via Coordinated NF ‐ κB Suppression and GSK3β /β‐Catenin Activation in Diabetic Osteoporosis

Diabetic osteoporosis (DOP) is characterized by chronic low‐grade inflammation and impaired bone formation. Pinoresinol diglucoside (PDG), a bioactive compound derived from Eucommia ulmoides Oliv., has shown therapeutic potential in metabolic bone disorders; however, its direct molecular targets and integrated mechanisms remain unclear. This study aimed to elucidate the metabolic basis and molecular targets through which PDG protects against high glucose (HG)‐induced osteoblast dysfunction and diabetic bone loss. Osteogenic effects of PDG were evaluated in HG‐exposed osteoblasts, with untargeted metabolomics, qPCR, Western blotting, molecular docking, SPR, and siRNA‐mediated knockdown applied to identify altered pathways and validate target necessity. In vivo, PDG was administered to db/db mice with DOP for 8 weeks, followed by micro‐CT, bone metabolism factors, histomorphometry, and immunofluorescence analyses. Metabolomic profiling identified arachidonic acid metabolism as the central pathway dysregulated in HG conditions and rescued by PDG. PDG directly bound and inhibited both p65 (NF‐κB) and GSK3β. Mechanistically, p65 knockdown abolished the anti‐inflammatory effect of PDG without affecting osteogenesis, whereas GSK3β knockdown abrogated β‐catenin activation and osteogenic differentiation without affecting anti‐inflammatory responses, indicating that they function as parallel and independent branches. Simultaneous knockdown of both completely blocked the functional recovery of osteoblast differentiation. In DOP mice, PDG significantly improved trabecular microarchitecture and bone metabolic homeostasis, reduced local PGE2 levels with an effect directly targeting bone, inhibited p65 nuclear translocation, and restored β‐catenin nuclear localization. PDG ameliorates DOP by dual targeting p65 and GSK3β, coordinately inhibiting NF‐κB‐mediated inflammation and activating the β‐catenin osteogenic program, highlighting its therapeutic potential for DOP.