Globotriaosylceramide Gb3 Influences Wound Healing and Scar Formation by Orchestrating Fibroblast Heterogeneity

Abstract Cutaneous fibroblast heterogeneity is mechanistically linked to wound repair outcomes and fibrotic progression, with glycosphingolipid metabolism emerging as a critical determinant of physiological fibroblast diversity. Through integrative analysis of spatiotemporal omics, lipidomics, and single‐cell RNA sequencing (scRNA‐seq) coupled with histological evaluation of clinical specimens, the functional involvement of globotriaosylceramide (Gb3) in dermal regeneration processes is systematically investigated. Comparative profiling reveals significant upregulation of Gb3 biosynthesis in superficial second‐degree burns (SSDB) relative to deep second‐degree burn (DSDB) injuries. Hexosaminidase subunit beta (HEXB) is identified as the exclusive differentially expressed Gb3 synthase distinguishing these injury subtypes. Functional validation through in vitro and in vivo models demonstrates that pharmacological suppression of HEXB‐mediated Gb3 synthesis exacerbates fibroblast‐to‐myofibroblast transdifferentiation, attenuated fibroblast growth factor 2 (FGF2) signal transduction, and ultimately potentiated fibrotic scarring. These findings establish a novel HEXB‐Gb3‐FGF2 regulatory axis governing fibroblast phenotypic plasticity in differential‐depth skin injuries, providing mechanistic insights for developing targeted antifibrotic therapies.