A panoramic analysis of keloid pathogenesis: multidimensional network regulation of genetics-immunity-metabolism-mechanical force.

Keloid, as a unique form of pathological scar, involves complex interactions across multiple dimensions in its pathogenesis, including genetic susceptibility, epigenetic regulation, immune microenvironment disorders, metabolic reprogramming, abnormal mechanical force transduction, and fine-tuning by non-coding RNAs. At the genetic level, alleles such as HLA-DRB1*15, HOX gene family, and high-frequency mutation genes including MUC4 constitute the foundation of congenital susceptibility; at the epigenetic level, reduced DNA methylation and imbalanced m6A modification promote fibrosis by regulating target genes such as COL1A1. In core signaling pathways, TGF-β/Smad, MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin pathways form a cross-talk network, driving persistent activation of fibroblasts and excessive extracellular matrix deposition. Characteristics of the immune microenvironment include M2-like macrophage polarization, Th17/IL-17 axis activation, and chronic low-grade inflammation maintained by inflammatory factor networks such as CXCL12. Regarding metabolic reprogramming, keloid cells exhibit "Warburg effect" features, prioritizing aerobic glycolysis while suppressing oxidative phosphorylation, alongside ferroptosis resistance and abnormal sphingolipid metabolism. Mechanical forces trigger the opening of mechanosensitive PIEZO1 ion channels, inducing abnormal calcium influx and subsequent YAP/TAZ nuclear translocation, which creates a self-amplifying vicious cycle alongside elevated matrix stiffness. Furthermore, lncRNAs, circRNAs, and miRNAs finely regulate the fibrotic process through competing endogenous RNA (ceRNA) networks and m6A modification-dependent mechanisms. The integration of these multidimensional mechanisms provides a theoretical basis for developing multi-target combination therapeutic strategies. Future research should promote the application of precision medicine in keloid management through multi-omics integration and artificial intelligence algorithms. Microenvironment; Metabolic reprogramming; Mechanical force transduction.