BACH1 is stabilized by vitamin E and attenuates the formation of hypertrophic scar through the Wnt/β-catenin pathway

The molecular drivers behind the pathogenesis of hypertrophic scar (HS) formation have not been determined in a comprehensive manner. Aside from that, no consensus has been reached on the role of vitamin E in HS. For this reason, we have probed the causal effect of 2940 plasma proteins and 187 diets on HS through Mendelian randomization (MR). Colocalization analysis, summary-data-based MR (SMR), heterogeneity in dependent instruments (HEIDI), and MR phenome-wide association study (MR-PheWAS) were employed to identify the potential drug targets of HS. Human Protein Atlas, differential expression analysis, weighted co-expression network analysis (WGCNA) and single-cell analysis were utilized to confirm the key biomolecules in HS. To investigate the roles of critical molecules, we harvested primary fibroblasts and conducted validations using both in vitro and in vivo animal models. We put forth a viewpoint that the transcription factor BACH1 is causally related to the onset of HS, is a protective factor for HS, and may serve as its therapeutic target. We further determined that BACH1 reveals substantial expression in human skin tissue. BACH1 is under-expressed in HS tissues and fibroblasts. We confirmed that BACH1 and vitamin E act in an anti-scar role in primary fibroblasts and animal models through the Wnt/β-catenin pathway. Overall, our results demonstrate that BACH1 has an inhibitory effect on HS, and vitamin E attenuates the formation of HS by stabilizing BACH1.

BACH1; Hypertrophic scar; Mendelian randomization; Plasma proteins; Vitamin E.