FOXM1 modulates keloid fibroblast proliferation and migration via the BMP4/Smad1/5/8 axis.

Abstract

Keloid is a refractory fibroproliferative skin disorder with unclear molecular pathogenesis. Here, we delineated FOXM1's role in regulating BMP4/Smad1/5/8 signaling and keloid fibroblast (KF) behavior via integrated bioinformatics and experiments. Bioinformatics analysis of GSE145725 identified differentially expressed genes and co-expression modules. PPI network analysis and module-trait correlation pinpointed BMP4 as a central hub gene. KnockTF 2.0 prediction and luciferase assays confirmed FOXM1 directly binds BMP4 promoter sites to repress its transcription. In vitro assays showed BMP4 overexpression inhibited KF proliferation, migration, and extracellular matrix synthesis by activating Smad1/5/8 phosphorylation. FOXM1 overexpression abrogated these effects via reduced Smad1/5/8 phosphorylation, which was validated by functional rescue experiments. In summary, our findings unravel a novel FOXM1-BMP4-Smad1/5/8 regulatory circuitry in keloid pathogenesis, providing new mechanistic insights and highlighting FOXM1 as a promising therapeutic target for this recalcitrant disorder.