Chrysophanol Attenuates Glucocorticoid‐Induced Osteoporosis by Targeting the E74 ‐Like Factor 5/Osteoglycin‐Regulated PI3K / AKT / mTOR Signaling Axis: An In Vitro and In Vivo Study

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, characterized by severe impairment of osteoblast function and increased bone fragility. Current therapeutic options inadequately address glucocorticoid (GC)-induced osteoblast apoptosis and suppress osteogenesis, highlighting the need for novel targeted interventions. To explore the molecular pathogenesis of GIOP and identify therapeutic targets, we performed integrated transcriptomic analysis, bioinformatics approaches, and multiple experimental validation methods. We demonstrate that dexamethasone (DEX), a prototypical GC, robustly upregulates osteoglycin (OGN) expression in both cellular and animal models. Crucially, the transcription factor ELF5 functions as a critical transcriptional repressor of OGN, counteracting DEX effects. ELF5-mediated OGN repression is essential for maintaining pro-survival PI3K/AKT/mTOR signaling integrity in osteoblasts. Molecular docking confirmed stable, high-affinity binding between the natural compound chrysophanol and OGN. Functionally, chrysophanol effectively antagonized DEX-induced OGN elevation and mitigated osteoblast apoptosis. This work is the first to define a role for the DEX-OGN-ELF5 axis in PI3K/AKT/mTOR signaling as critical for osteoblast survival in GIOP. Chrysophanol, as a novel natural compound targeting this OGN-centric axis, presents a promising and potentially safer therapeutic alternative to bisphosphonates, which are associated with risks like atypical femoral fractures and osteonecrosis of the jaw. Our findings offer novel insights into the molecular pathogenesis of GIOP, identify a potential druggable ELF5/OGN/PI3K/AKT/mTOR signaling axis, and establish a basis for future translational research in GC-induced bone diseases.