Silibinin accelerates diabetic wound healing through PI3K/Akt-mediated immunomodulation-angiogenesis crosstalk

Diabetic wound healing remains clinically challenging due to microangiopathy and immune microenvironment dysregulation. Silibinin (SIL), a natural polyphenolic flavonoid with multiple pharmacological properties, including anti-inflammatory, antioxidant, endothelial protective, and immunomodulatory effects, has demonstrated therapeutic potential for diabetic wounds, yet its efficacy and mechanisms require further elucidation. This study evaluated SIL's effects on wound healing in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice and elucidated its underlying molecular mechanisms. Network pharmacology and transcriptomics identified EGFR, VEGFR2, BCL2, ITGB1, and the PI3K/Akt pathway as key targets, with molecular docking confirming SIL's high-affinity binding to these targets. In HFD/STZ-induced diabetic mice, SIL accelerated wound closure by enhancing re-epithelialization, collagen deposition, and granulation tissue formation. SIL promoted M1-to-M2 macrophage polarization (reducing CD86 and elevating CD206), suppressed pro-inflammatory cytokines (TNF-α/IL-1β), and increased anti-inflammatory factors (IL-4/IL-10). Angiogenesis was robustly stimulated, evidenced by elevated microvascular density and upregulated expression of VEGF, CD31, and α-SMA, with improved microcirculatory perfusion confirmed by laser speckle contrast imaging (LSCI). Mechanistically, RNA sequencing and Western blotting validated PI3K/Akt pathway activation, enhancing effector proteins linked to cell survival and vascular regeneration. These findings demonstrate SIL accelerates diabetic wound healing through PI3K/Akt-mediated immunomodulation-angiogenesis crosstalk, highlighting its potential as a natural therapeutic agent for diabetic wounds.