Deciphering the interplay: circulating cell-free DNA, signaling pathways, and disease progression in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lung disease with an unknown etiology and a short survival rate. There is no accurate method of early diagnosis, and it involves computed tomography (CT) or lung biopsy. Since diagnostic methods are not accurate due to their similarity to other lung pathologies, discovering new biomarkers is a key issue for diagnosticians. Currently, the use of ccf-DNA (circulating cell-free deoxyribonucleic acid) is an important focus due to its association with IPF-induced alterations in metabolic pathways, such as amino acid metabolism, energy metabolism, and lipid metabolism pathways. Other biomarkers associated with metabolic changes have been found, and they are related to changes in type II/type I alveolar epithelial cells (AECs I/II), changes in extracellular matrix (ECM), and inflammatory processes. Currently, IPF pathogenetic treatment remains unknown, and the mortality rates are increasing, and the patients are diagnosed at a late stage. Signaling pathways and metabolic dysfunction have a significant role in the disease occurrence, particularly the transforming growth factor-β (TGF-β) signaling pathway, which plays an essential role. TGF-β, Wnt, Hedgehog (Hh), and integrin signaling are the main drivers of fibrosis. These pathways activate the transformation of fibroblasts into myofibroblasts, extracellular matrix (ECM) deposition, and tissue remodeling fibrosis. Therapy targeting diverse signaling pathways to slow disease progression is crucial in the treatment of IPF. Two antifibrotic medications, including pirfenidone and nintedanib, are Food and Drug Administration (FDA)-approved for treatment. ccf-DNA could become a new biomarker for IPF diagnosis to detect the disease at the early stage, while FDA-approved therapies could help to prevent late conditions from forming and decrease mortality rates.