Scutellarin Alleviates Bone Marrow Mesenchymal Stromal Cellular Senescence via the Ezh2‐Nrf2 Signalling Axis in Diabetes‐Induced Bone Loss

Currently, there is no specific treatment for diabetes-induced osteoporosis (DOP). Our study identified diabetes-induced cellular senescence, marked by elevated activity of senescence-associated β-galactosidase. Targeting senescent cells holds promise for osteoporosis treatment. We demonstrated that scutellarin (SCU) effectively mitigated bone loss in DOP mice, and co-treatment with SCU significantly reduced diabetes-induced senescence in LepR+MSCs. Furthermore, our research highlighted the role of Nrf2 in SCU's anti-senescence effects on bone. The deletion of Nrf2 impaired SCU's ability to alleviate DOP. Mechanistically, SCU enhances Ezh2 expression and increases H3K27me3 activity at the Keap1 promoter region, leading to Keap1 repression and enhanced Nrf2-ARE signalling. Additionally, SCU notably inhibited cellular senescence and diabetes-related osteoporosis, these effects were significantly reduced in Ezh2^LepRcre conditional knockout models. These findings suggest that the Ezh2-Nrf2 signalling axis is crucial for mediating SCU's beneficial effects in this context. Overall, our discoveries provide insights into the mechanisms underlying DOP and propose a potential preventive strategy for this condition.