Viridicatol from the Deep‐Sea‐Derived Fungus Alleviates Bone Loss by Targeting the Wnt/SHN3 Pathway

As an enticing bone anabolic target, short-term inhibition of Schnurri-3 (SHN3) resulted in high-bone mass due to augmented osteoblast activity. However, no studies are conducted to identify natural products targeting SHN3 inhibition. Herein, a screening strategy for the discovery of marine compounds that facilitate osteoblast differentiation by targeting SHN3 silencing is presented. One leading quinolinone alkaloid, viridicatol (VDC), isolated from deep-sea-derived fungus, vigorously promotes osteogenic differentiation via the Wnt/SHN3 signaling pathway in osteoblasts, thereby preventing osteoporosis while enhancing bone-fracture healing in a mouse model. Subsequently, the SDSSD (Ser, Asp, Ser, Ser, Asp) is further employed to engineer bone-targeting nanovesicles (BT-NVs) for the optimal delivery of VDC to osteoblasts, which mitigates the bone loss observed in a severe osteogenesis imperfecta model. Hence, these results initially uncover a promising marine natural product, VDC, targeting the Wnt/SHN3 pathway for the treatment of bone loss and highlighting its translational potential in clinical applications.