Loureirin B Accelerates Diabetic Wound Healing by Promoting TGFβ/Smad‐Dependent Macrophage M2 Polarization: A Concerted Analytical Approach Through Single‐Cell RNA Sequencing and Experimental Verification

ABSTRACT Diabetic wound (DW) represent a significant clinical challenge and often fail to heal effectively. Loureirin B (LB), a flavonoid extracted from dragon's blood, has shown potential by influencing macrophage polarization and promoting wound healing. However, its mechanisms and efficacy in DW remain to be explored. This study employed single‐cell RNA sequencing to analyze the classification of cells in diabetic foot ulcers and to identify the related mechanisms influenced by macrophages. Molecular docking was used to predict the interactions of LB with key proteins in the TGFβ/Smad signaling pathway. The effects of LB on macrophage polarization and wound healing were further validated through in vitro and in vivo experiments using a DW model. Single‐cell analysis identified specific macrophage subtypes involved in the DW healing process and highlighted the role of the TGFβ/Smad pathway. Molecular docking suggested the potential action within the TGFβ/Smad pathway. In vitro studies showed that under high glucose conditions, LB promoted macrophage polarization from pro‐inflammatory M1 to healing‐promoting M2 and ECM production in fibroblasts by activating TGF‐β/Smad signaling. In vivo, LB treatment enhanced wound healing rates in diabetic mice and promoted macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF‐β/Smad signaling. LB regulates macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF‐β/Smad signaling to promote DW healing. These findings suggest that LB could be a potential therapeutic agent for improving DW healing, emphasizing the need for further clinical studies to explore its efficacy and mechanisms in human subjects.