Broussonin A Attenuates Type 2 Diabetic Osteoporosis by Reactivating JAK2 / STAT3 Signaling to Inhibit Ferroptosis in BMSCs

ABSTRACT Type 2 diabetic osteoporosis (T2DOP) significantly impairs bone health, partially through ferroptosis triggered by glucolipotoxicity. However, therapeutic strategies targeting this process remain largely unexplored. Broussonin A (BRA), a natural antioxidant compound, shows potential for treating bone metabolic disorders, yet its specific effects on T2DOP are unclear. This study aimed to examine whether BRA inhibits ferroptosis and restores bone quality under type 2 diabetic conditions. A rat model of T2DOP was established by administering streptozotocin (STZ) combined with a high‐fat dietary regimen. Additionally, an in vitro model was developed through the exposure of bone marrow mesenchymal stem cells (BMSCs) to high‐glucose/high‐lipid (HGHF) conditions. Intracellular Fe 2+ and lipid peroxidation levels were determined using FerroOrange and C11‐BODIPY staining techniques separately. Mitochondrial integrity and function were assessed via JC‐1 staining and ultrastructural examination. Furthermore, assays for osteogenic differentiation, Western blotting (WB), and immunofluorescence (IF) analyses were performed. The results showed that BRA markedly reduced cytotoxicity induced by high‐glucose/high‐lipid exposure, decreased lipid peroxidation and Fe 2+ overload, restored mitochondrial integrity and antioxidant enzyme activities, and rescued impaired osteogenic function in BMSCs. In vivo administration of BRA maintained femoral trabecular microarchitecture without observable toxicity to major organs. Network pharmacology analysis and cellular thermal shift assays identified the JAK2/STAT3 signaling pathway as the direct molecular target. Treatment with BRA effectively restored the phosphorylation states of JAK2 and STAT3, leading to an elevation in GPX4 protein expression. Importantly, knockdown of STAT3 through siRNA interference abolished these protective effects. Taken together, these findings indicate that BRA mitigates T2DOP by reactivating the JAK2/STAT3 signaling axis, thereby suppressing ferroptosis.