Abstract / Summary
Delayed healing of diabetic wounds arises from a self-sustaining pathological microenvironment featuring persistent inflammation, excessive matrix degradation, impaired angiogenesis, and insufficient collagen deposition, and current single-process interventions remain unsatisfactory. Red yeast rice, produced by fermentation of rice with Monascus spp., is a traditional fermented product with documented anti-inflammatory and antioxidant activities; however, its direct extract is dominated by macromolecular and bound-state constituents with low release efficiency and poor skin permeation, which restricts its topical application. In this study, an enzymatic hydrolysate of red yeast rice (RYR-EH) was prepared by composite enzymatic hydrolysis, and the compositional changes induced by hydrolysis were characterized by widely targeted UPLC-MS/MS metabolomics. A total of 810 metabolites were detected, among which 199 showed differential accumulation after hydrolysis (179 upregulated and 20 downregulated; FC ≥ 2 or ≤0.5, VIP ≥ 1, and p < 0.05); the differential metabolites were significantly enriched (FDR < 0.05) in purine metabolism, nucleotide metabolism, ABC transporters, and the cGMP-PKG signaling pathway, a pattern consistent with hydrolysis-driven release of free amino acids, small peptides, and other low-molecular-weight constituents. In type 2 diabetic mice induced by a high-fat diet combined with low-dose streptozotocin, topical RYR-EH (2% and 5%) significantly accelerated the closure of full-thickness excisional wounds, with the 5% formulation showing more advanced closure than the 2% formulation and an effect approaching that of recombinant human epidermal growth factor (rhEGF). At the day-14 endpoint, RYR-EH treatment was associated with enhanced re-epithelialization, lower TNF-α, IL-6, and IL-1β levels in both wound tissue and serum, reduced MMP-2 and MMP-9 immunoreactivity, reduced Ki67-positive cellularity in the late-stage wound bed, increased Collagen I/III deposition, and increased VEGF/CD31 immunoreactivity. These results demonstrate that RYR-EH exerts multi-process reparative effects on diabetic wounds, simultaneously attenuating inflammation, restraining excessive matrix degradation, promoting angiogenesis, and restoring collagen deposition, and support RYR-EH as an effective multi-process topical agent for diabetic wound healing.