Branch-chain amino acid accumulation: multiple roles in the pathogenesis of diabetic foot ulcers

Diabetic foot ulcers (DFUs) are devastating complications of diabetes, defined by impaired healing, high amputation rates, and substantial mortality, with pathogenesis rooted in interconnected metabolic, immune, and vascular dysregulation. Serum metabolomic profiling identifies elevated branched-chain amino acid (BCAA) levels in DFU patients, yet the metabolic mechanisms linking BCAA dysregulation to DFU remain unexplored. This review systematically presents a causal framework: impairment of the BCAA metabolic process (downregulation of BCKDH in skeletal muscle/fat tissue), dysbiosis of the intestinal microbiota leading to systemic accumulation of BCAA, and subsequent activation of the mTORC1/NF-κB signaling cascade. This triggers insulin resistance, mitochondrial dysfunction, and oxidative stress, causing macrophages to polarize to the pro-inflammatory M1 phenotype, disrupting the functions of NK cells and neutrophils, and inhibiting angiogenesis mediated by HIF-1α/VEGF forming a self-perpetuating metabolic-immune-vascular vicious cycle, thereby delaying the wound healing process. This review aims to provide a metabolism-centered framework for understanding the pathogenesis of DFU and for informing future diagnostic and therapeutic research.