Diacerein protects against Ovariectomy-Induced bone loss via reversal of NRF2 epigenetic suppression.

Osteoporosis (OP) is a prevalent degenerative musculoskeletal disorder in middle-aged and elderly populations, characterized by reduced bone mineral density and an increased risk of fragility fractures. Its pathogenesis is closely linked to oxidative stress imbalance; however, effective long-term therapeutic options remain limited. Here, we report that diacerein, a clinically used drug for osteoarthritis, significantly ameliorates OVX (ovariectomy)-induced bone loss and abnormal bone metabolism. Mechanistically, we demonstrate that diacerein activates the transcription and activity of NRF2 (nuclear factor erythroid 2-related factor 2), a central regulator of the antioxidant response, leading to the restoration of cytoprotective protein expression and thereby exerting protective effects against osteoporosis. The beneficial effects of diacerein on bone protection were largely abolished in Nfe2l2 knockout mice, further underscoring the essential role of NRF2. Further investigation revealed that diacerein is metabolized in vivo into rhein, which exerts potent epigenetic activity. The upregulation of NRF2 appears to be primarily mediated through rhein's inhibition of DNA methyltransferases (DNMTs) 1 and 3a. In summary, our study suggests that diacerein, a drug with a well-established safety profile and suitability for long-term use, represents a promising therapeutic candidate for the treatment of osteoporosis.