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Current therapeutic options inadequately address glucocorticoid (GC)\u2010induced 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\u2010mediated OGN repression is essential for maintaining pro\u2010survival PI3K\/AKT\/mTOR signaling integrity in osteoblasts. Molecular docking confirmed stable, high\u2010affinity binding between the natural compound chrysophanol and OGN. Functionally, chrysophanol effectively antagonized DEX\u2010induced OGN elevation and mitigated osteoblast apoptosis. This work is the first to define a role for the DEX\u2010OGN\u2010ELF5 axis in PI3K\/AKT\/mTOR signaling as critical for osteoblast survival in GIOP. Chrysophanol, as a novel natural compound targeting this OGN\u2010centric 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\u2010induced bone diseases.<\/jats:p>","DOI":"10.1002\/ptr.70257","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T08:36:13Z","timestamp":1770626173000},"page":"2143-2165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chrysophanol Attenuates Glucocorticoid\u2010Induced Osteoporosis by Targeting the\n                    <scp>E74<\/scp>\n                    \u2010Like Factor 5\/Osteoglycin\u2010Regulated\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>mTOR<\/scp>\n                    Signaling Axis: An In\u00a0Vitro and In\u00a0Vivo 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