Impaired branched-chain amino acid catabolism serves as a metabolic hallmark and therapeutic target in keloids.

Abstract

Keloids are refractory proliferative scars driven by aberrant collagen deposition and metabolic remodeling. While branched-chain amino acids (BCAAs) are known to influence skin collagen synthesis, their specific roles and underlying regulatory mechanisms in keloid pathogenesis remain largely unexplored. An integrated analysis of five transcriptomic datasets was conducted to characterize BCAA catabolic gene expression in keloids. We performed functional enrichment analysis, protein-protein interaction network construction, microenvironment profiling, and gene set variation analysis. Circulating and tissue BCAA levels were quantified in clinical samples. The functional impact of specific BCAAs and the metabolic enhancer BT2 on keloid fibroblasts (KFs) proliferation and extracellular matrix (ECM) production was assessed in vitro. The study reveals a systemic downregulation of 72.5% of BCAA catabolic genes in keloids, establishing impaired BCAA catabolism as a distinct metabolic hallmark. This comprehensive metabolic blockade creates a permissive metabolic microenvironment characterized by the accumulation of BCAAs. Molecular classification identifies a distinct BCAA catabolic-defective subtype; this cluster, defined by the coordinated dysregulation of multiple catabolic enzymes, correlates with enhanced epithelial-mesenchymal transition and angiogenic activity. Clinical validation confirms significantly higher circulating and tissue levels of BCAAs in keloid patients. In vitro experiments identify leucine as the primary metabolic effector that drives KFs proliferation and ECM deposition, a phenotype that can be effectively rescued by pharmacological enhancement of BCAA catabolism. This study highlights the importance of impaired BCAA catabolism, particularly leucine accumulation in keloid formation, providing new insights into keloid pathogenesis and potential therapeutic targets.