Cinnamaldehyde promotes diabetic wound healing via synergetic effects of AGE/RAGE-mediated macrophage polarization affecting fibroblast activation and angiogenesis, and Nrf2-dependent antioxidants.

Diabetic foot ulcer (DFU), a serious complication of diabetes mellitus (DM), is characterized by delayed wound healing and is a major cause of nontraumatic amputation. This study investigated cinnamaldehyde's regulatory effect on DFU and its underlying mechanisms. A DFU model was established in BALB/c mice using streptozotocin (STZ); mice received cinnamaldehyde (100 mg/kg, intraperitoneally). In vitro, cells were treated with 10 μM cinnamaldehyde. Histology, ELISA, immunofluorescence, western blotting, tube formation, and transwell assays were employed. Results showed cinnamaldehyde effectively improved DFU healing, evidenced by accelerated wound closure, reduced inflammatory infiltration, increased CD31 expression, and lower oxidative stress. Mechanistically, cinnamaldehyde suppressed Advanced Glycation End products (AGE)/Receptor for Advanced Glycation End products (RAGE) signaling and its downstream proteins p-IKBα and p-NF-κB p65 (supported by GSE134431 dataset analysis). Cinnamaldehyde reversed STZ-induced shifts in macrophage populations, decreasing M1-like (CD86+) and increasing M2-like (CD206+) macrophages. This M2 polarization was RAGE-dependent, as RAGE overexpression (OE-RAGE) counteracted cinnamaldehyde's effects on iNOS and Arg-1 levels in macrophages. These findings indicate cinnamaldehyde facilitated M2 macrophage polarization in DFU wounds via AGE/RAGE signaling. Furthermore, cinnamaldehyde-induced, AGE/RAGE-mediated macrophage polarization subsequently promoted human dermal fibroblast (HDF) proliferation, migration, and angiogenesis. Importantly, cinnamaldehyde also modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway under high glucose conditions, contributing to increased antioxidant signaling activity. Our work reveals cinnamaldehyde promotes diabetic wound healing through synergistic effects involving AGE/RAGE-mediated macrophage polarization (affecting fibroblast activation and angiogenesis) and Nrf2-dependent antioxidant responses.