Salidroside derivative SHPL-49 accelerates cutaneous wound healing in diabetic mice by modulating macrophage-mediated...

Impaired wound healing represents a major complication of diabetes, yet effective therapeutic options remain limited. Our research group has developed a salidroside derivative, SHPL-49, which exhibits antioxidant, anti-inflammatory, and pro-angiogenic properties. We hypothesized that SHPL-49 may promote diabetic wound healing through the modulation of macrophage-mediated immune responses and fibroblast activity. In vivo studies revealed that SHPL-49 significantly accelerated wound closure in diabetic mice, with enhanced granulation tissue formation and extracellular matrix (ECM) deposition. Mechanistically, SHPL-49 induced M2 polarization of wound-associated macrophages, which subsequently secreted TGF-β1 to activate the TGF-β1/Smad2/3 pathway in fibroblasts. In vitro experiments further confirmed that SHPL-49 directly promoted M2 polarization in RAW 264.7 macrophages, as evidenced by increased CD206 expression and TGF-β1 secretion. The conditioned medium from SHPL-49-activated macrophages promoted Smad2/3 phosphorylation in L929 fibroblasts, thereby stimulating their proliferation, migration, and upregulating the expression of collagen I/III, α-SMA, and TGFβRI. Collectively, our findings suggest that SHPL-49 is a promising therapeutic candidate for diabetic wound healing, functioning through a macrophage-to-fibroblast signaling axis: it polarizes macrophages toward an M2 phenotype, which subsequently release TGF-β1 to enhance fibroblast function via the Smad2/3 signaling pathway. This study establishes a theoretical foundation for the future exploration and development of novel therapeutic indications for SHPL-49.