CTHRC1: An Emerging Hallmark of Pathogenic Fibroblasts in Lung Fibrosis

Pulmonary fibrosis is a chronic, progressive lung disease characterized by irreversible scarring of the lung tissue. This condition is marked by an excessive buildup of the extracellular matrix (ECM) due to the abnormal activation of myofibroblasts within the alveoli. Transforming growth factor beta (TGF-β) signaling is a key driver of this fibrotic process, as it stimulates the overproduction of ECM, leading to scar formation and lung damage. A crucial target of TGF-β signaling in fibrosis is Collagen Triple Helix Repeat Containing 1 (CTHRC1), a secreted glycoprotein that plays a vital role in ECM deposition and wound repair. TGF-β regulates CTHRC1 at the transcriptional level in response to tissue injury, influencing the wound healing process through its functional activity. CTHRC1 is also thought to be important in restoring and maintaining tissue homeostasis after wound closure by modulating both the TGF-β and canonical Wnt signaling pathways. This dual role suggests that CTHRC1 is involved in tissue remodeling and maintaining homeostasis. However, abnormal CTHRC1 expression in pathogenic fibroblasts has recently been identified as a key feature of fibrosis in various organs and tissues. Recent studies highlighted in this review suggest that CTHRC1 could serve as a diagnostic and prognostic biomarker for fibrosis in conditions such as idiopathic pulmonary fibrosis, systemic sclerosis, and post-COVID-19 lung fibrosis. Notably, CTHRC1 expression responds to antifibrotic drugs targeting the TGF-β pathway, such as pirfenidone and bexotegrast, indicating its potential as a marker for treatment efficacy. These findings point to CTHRC1 as a promising avenue for improving the diagnosis and treatment of lung fibrosis.