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

## TL;DR

This study shows how a lipid called Gb3 helps control wound healing and scarring by influencing different types of skin cells.

## Contribution

The study identifies a new regulatory pathway involving Gb3, HEXB, and FGF2 in fibroblast behavior during wound healing.

## Key findings

- Gb3 biosynthesis is significantly upregulated in superficial second-degree burns compared to deep burns.
- Pharmacological suppression of HEXB increases fibrotic scarring by altering fibroblast behavior.
- The HEXB-Gb3-FGF2 axis regulates fibroblast plasticity in skin injuries of different depths.

## 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.

In superficial second‐degree burn wounds, Gb3 turns on genes related to papillary cells through the FGF2 signaling pathway. This increases the ability of cells to break down fibrin and decreases fibrosis, which ultimately prevents scar formation in burn injuries. The deep second‐degree burn wounds augment the fibrotic capacity of the cells, resulting in the development of hypertrophic scars. Created in BioRender.