Study on the mechanism of traditional chinese medicine compound Shixiang Plaster improving diabetic wound healing through MAPK regulation of macrophage polarization.

Abstract

The healing impairment of diabetic foot ulcers (DFU) is closely related to chronic inflammation and the imbalance of M1/M2 polarization of macrophages. This study aims to elucidate the mechanism by which the traditional Chinese medicine compound Shixiang Plaster (SXP) promotes wound healing in diabetes by regulating the MAPK signaling pathway and modulating macrophage polarization. A full-thickness skin defect model in streptozotocin (STZ)-induced diabetic mice was established and divided into the control group, model group, SXP group, and basic fibroblast growth factor (BFGF) group. Histological, immunofluorescence, qRT-PCR, Western Blot, and metabolomics analyses were conducted. The results showed that SXP significantly accelerated wound healing (P < 0.05), promoted re-epithelialization and collagen deposition, and reduced inflammatory infiltration. The mechanism lies in its effective inhibition of M1-type macrophage (F4/80⁺CD86⁺) infiltration and promotion of M2-type (F4/80⁺CD206⁺) polarization, accompanied by a decrease in serum pro-inflammatory factors (IL-6, TNF-α) and an increase in anti-inflammatory factors (IL-10). At the molecular level, SXP significantly inhibited the expression of MAPK8 (JNK), p38, and p44/42 (ERK) at both transcriptional and protein levels, and reduced their phosphorylation activities (p-p38, p-p44/42). Metabolomics analysis suggested that the flavonoid components in SXP (kaempferol, daidzein) might indirectly affect the MAPK pathway by regulating the redox balance. This study reveals that SXP improves diabetic wound healing, which is associated with the inhibition of the MAPK signaling axis and a shift in macrophage polarization. Metabolomics analysis identified altered levels of flavonoids (e.g., kaempferol, daidzein) in wound tissue, suggesting their potential involvement in the observed effects via the "components-MAPK-macrophage" cascade. This multi-target mode of action provides a new therapeutic perspective for DFU.