SOX4 is a transcriptional activator for CTHRC1 in lung fibroblast activation

Collagen triple helix repeat containing 1 (CTHRC1) has recently emerged as a hallmark of fibroblast activation in pulmonary fibrosis. However, the underlying transcriptional regulatory mechanisms remain incompletely understood. Analysis of bulk datasets (GSE124685 and GSE169500) and single-cell RNA sequencing dataset (GSE135893) revealed that CTHRC1 and SRY-related HMG-box transcription factor 4 (SOX4) were upregulated and positively correlated in fibrotic lungs, with both genes predominantly co-localized in activated fibroblast subpopulations. Consistently, their expression was elevated in the TGFβ1-induced MRC5 fibroblasts. JASPAR analysis predicted SOX4 as a potential transcription factor for CTHRC1, and luciferase reporter assays, mutational analysis, and chromatin immunoprecipitation (ChIP) confirmed that SOX4 directly binds to the CTHRC1 promoter to activate its transcription. siRNA-mediated knockdown and overexpression experiments further demonstrated that SOX4 positively regulates CTHRC1 expression at both mRNA and protein levels. Functional assays showed that SOX4 silencing attenuated TGFβ1-induced collagen deposition, fibroblast migration and proliferation. Collectively, these findings identify SOX4 as a transcriptional activator of the CTHRC1 in lung fibroblast, and suggest that the SOX4-CTHRC1 regulatory axis may represent a potential therapeutic target for intervening in fibroblast activation.