Discovery of β-sitosterol's effects on molecular changes in rat diabetic wounds and its impact on angiogenesis and macrophages.

Diabetes care, particularly for diabetic foot ulcers (DFUs)-related complications, increases treatment costs substantially. Failure to provide timely and appropriate treatment for severe DFUs significantly increases amputation risk. Neovascularization and macrophage polarization play an important role in diabetic wound healing during different stages of the wound repair process. Therefore, a new treatment method that promotes neovascularization and macrophage polarization may accelerate diabetic wound healing. β-sitosterol possesses anti-inflammatory, lipid-lowering, and antidiabetic properties. However, its therapeutic potential in diabetic wound healing remains underexplored. This study evaluated the healing effects of β-sitosterol on diabetic ulcer wounds in rats. We found that β-sitosterol can promote angiogenesis, alternatively activated macrophages (M2 macrophage) proliferation, and collagen synthesis in diabetic wounds. Transcriptomics analysis and proteomics analysis revealed that MAPK, mTOR and VEGF signaling pathways were enriched in β-sitosterol-treated wounds. Molecular docking revealed Ndufb5 maybe the target of β-sitosterol-treated wounds. Our findings confirm the significant diabetic wound healing effects of β-sitosterol in a rat model. β-sitosterol treatment to diabetic wounds accelerates wound healing through promoting M2 macrophage proliferation and angiogenesis. Interestingly, we also found that the process of M2 macrophage proliferation accompanies angiogenesis. Thus, β-sitosterol may be a promising therapeutic approach to enhance diabetic wound healing and reduce amputation in diabetes.