Irisolidone enhances osteoblast differentiation via the AMPK-ULK1-autophagy Axis to accelerate osteoporotic fracture repair

The global increase in osteoporotic fractures, characterized by delayed healing and impaired bone regeneration, presents a major public health issue. Irisolidone, a flavonoid from traditional Chinese medicine with a proven safety record, shows promise for bone health, though its role in osteoporotic fracture repair remains largely unexplored. This study aimed to investigate whether Irisolidone enhances osteoporotic fracture repair by promoting osteoblast differentiation through the activation of the AMPK-ULK1-autophagy pathway. RNA-Seq was employed to investigate the effects of Irisolidone on osteoblasts, revealing that Irisolidone enhances osteoblast differentiation by regulating autophagy-related pathways. These transcriptomic findings were validated in vitro using osteoblast cultures treated with Irisolidone, with Autophagy and osteogenic markers confirmed through Western blot, qPCR, and immunofluorescence analysis. The role of Autophagy in Irisolidone's effects was confirmed using Bafilomycin A1 and shAMPK transfection. In vivo, Irisolidone's impact on fracture healing was assessed in normal and osteoporotic mice through micro-CT, histology, and immunohistochemistry. Our findings show that Irisolidone accelerates fracture healing in both normal and osteoporotic mice by promoting osteoblast differentiation through the activation of the AMPK-ULK1-autophagy pathway. In vitro, Irisolidone enhanced osteoblast differentiation and Autophagy, while in vivo, it increased bone mass and improved fracture healing, demonstrating its therapeutic potential for improving bone density and healing osteoporotic fractures. In summary, Irisolidone promotes osteoporotic fracture repair by enhancing osteoblast differentiation through the activation of the AMPK-ULK1-autophagy axis. These findings suggest that Irisolidone could serve as a promising therapeutic agent for osteoporotic fractures by leveraging Autophagy.

AMPK-ULK1-autophagy Axis; Irisolidone; Osteoblast differentiation; Osteoporotic fracture; Osteoprosis.