From fibrosis to malignancy: Insights into the genetic landscape linking idiopathic pulmonary fibrosis and lung cancer

Abstract

Idiopathic pulmonary fibrosis (IPF) markedly increases the risk of developing lung cancer, particularly non-small cell lung cancer (NSCLC); however, the molecular mechanisms underlying this progression remain poorly understood. This review indicates current findings on shared genetic alterations and mechanistic pathways that link chronic fibrotic remodeling with oncogenesis. By systematically analyzing recent transcriptomic and in silico studies, key molecular drivers were identified across five functional domains: extracellular matrix remodeling (e.g., MMP1, SPP1), chronic inflammation (e.g., C1q, CCL13), oxidative stress and genomic instability (e.g., TP53, SETD2), surfactant dysfunction (e.g., SFTPC, SFTPB), and dysregulated growth factor signaling (e.g., EGFR, PIK3CA). Emerging candidates such as PLA2G7 and SEMA6B show potential roles in immune modulation and epithelial plasticity. Enrichment analyses confirm the involvement of these genes in extracellular matrix (ECM) remodeling, collagen degradation, integrin signaling, receptor tyrosine kinase signaling, and cytokine signaling. Although the findings remain correlative, they point to a shared molecular landscape underlying fibrotic and neoplastic transformation. Future studies integrating longitudinal cohorts and functional validation are essential to refine biomarker strategies and therapeutic targets for patients with fibrotic lung disease at risk of malignancy.