Screening of a quinonoid compounds library identifies decylubiquinone as an antioxidant and anti-apoptotic agent against glucocorticoid-induced osteoporosis via CD39/CD73/adenosine axis.

Glucocorticoid-induced osteoporosis (GIOP) is a prevalent and serious side effect of long-term glucocorticoid therapy, characterized by elevated oxidative stress and profound suppression of bone formation. There is a lack of therapies that effectively target the underlying oxidative stress and impaired osteogenesis simultaneously. In this study, we aimed to identify novel therapeutic agents from a library of quinonoid compounds. Using a high-throughput screen with Runx2 promoter-luciferase reporter cells, we identified decylubiquinone (DUB) as a potent candidate that counteracted dexamethasone (Dex)-induced oxidative stress and osteogenic suppression in bone marrow mesenchymal stem cells (BMSCs). In a murine GIOP model, DUB administration significantly alleviated bone loss, reduced oxidative stress, and inhibited osteoblast apoptosis. Mechanistically, DUB restored the glucocorticoid-impaired CD39/CD73/adenosine (ADO) axis, thereby elevating extracellular ADO levels. ADO subsequently exerted dual protective effects: it attenuated oxidative stress and apoptosis induced by glucocorticoids, and it activated the adenosine A(2b) receptor (A(2b)R), triggering the downstream cAMP/PKA/CREB signaling cascade to drive osteogenic gene expression. Genetic knockdown of CD39, CD73, or A(2b)R abolished the beneficial effects of both DUB and exogenous ADO. Furthermore, we developed bone-targeted DUB-loaded liposomes (DUB@TLip), which markedly enhanced the in vivo therapeutic efficacy of DUB. In summary, our study not only identifies DUB as a promising anabolic agent against GIOP but also reveals a novel mechanistic link between purinergic signaling and bone redox homeostasis, highlighting the therapeutic potential of targeting the CD39/CD73/ADO axis for treating this and potentially other oxidative stress-associated skeletal disorders.