Exploring the Anti‐inflammatory Molecular Mechanism of L‐shikonin in Promoting Diabetic Wound Healing by Modulating the Janus Kinase/Phosphatidylinositol‐3‐kinase/Protein Kinase B/Vascular Endothelial Growth Factor Pathway Based on Network Pharmacology

Diabetic foot ulcers (DFUs) exhibit impaired healing due to disrupted macrophage polarization, wherein persistent hyperglycemia inhibits the critical M1-to-M2 phenotypic transition, sustaining a pro-inflammatory microenvironment. This investigation elucidates the therapeutic potential of L-shikonin (L-SK), a bioactive phytochemical derived from comfrey with established immunomodulatory properties. In a streptozotocin-induced diabetic murine model, L-SK treatment significantly enhanced wound closure through coordinated anti-inflammatory effects (downregulation of CD86 and tumor necrosis factor-α) and pro-regenerative outcomes (increased collagen deposition and CD31-mediated angiogenesis). At the molecular level, L-SK administration facilitated macrophage polarization towards the regenerative M2 phenotype (upregulated CD163 expression) while activating the pivotal Janus Kinase/phosphatidylinositol-3-kinase/protein kinase B/vascular endothelial growth factor (JAK/PI3K/AKT/VEGF) signaling cascade, as evidenced by enhanced phosphorylation of AKT and PI3K alongside elevated VEGF production. Complementary in vitro studies using human monocytic leukemia cells-derived macrophages confirmed these mechanistic findings, demonstrating consistent modulation of macrophage differentiation markers and secretory profiles. These results position L-SK as a multifaceted therapeutic agent capable of concurrently addressing the immunological and vascular deficiencies characteristic of DFUs, through its dual capacity for macrophage phenotype reprogramming and angiogenic pathway activation. The study provides compelling preclinical evidence for L-SK's potential application in diabetic wound management strategies.