Targeted delivery of viridicatol from deep-sea-derived fungus for ameliorate bone loss through the SHN3/SLIT3 pathway

The adaptor protein Schnurri-3 (SHN3) is an attractive target for osteoporosis, fractures, and osteogenesis imperfecta, as short-term inhibition of SHN3 resulted in a high–bone mass due to augmented osteoblasts activity. However, there have been no reports of natural small molecules targeting SHN3 inhibition. Here, we report a screening strategy for the discovery of marine compounds that promoted osteoblast differentiation by targeting silencing SHN3. One lead quinolinone alkaloid named viridicatol (VDC), isolated from deep-sea-derived fungus, strongly promoted osteogenic differentiation and angiogenesis. Mechanistically, VDC promotes osteogenic activity and H-type angiogenesis through the SHN3/SLIT3 signaling pathway, ultimately achieving treatment for osteoporosis and fracture repair. These results firstly develop a promising marine natural product, VDC, that targets the SHN3/SLIT3 pathway for the treatment of osteoporosis and fractures, highlighting its translational potential in clinical applications.