Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia primarily affecting lung interstitium (Leon-Roman et al., 2022). Lung interstitium refers to structures between lung parenchyma (e.g., alveoli and bronchi), including alveolar wall tissues and regions between capillary endothelium and alveolar epithelium (Doshi et al., 2022). Hallmark of IPF is fibrosis of lung interstitium, which represents end stage of interstitial lung disease. This leads to progressive deterioration of respiratory function, manifesting as clinical symptoms such as dry cough, fatigue, and progressive exertional dyspnea (Huang and Tang, 2021, Podolanczuk et al., 2023, Glass et al., 2022). Although current treatment options for IPF are limited and prognosis remains poor (Benegas Urteaga et al., 2022), early diagnosis can effectively delay disease progression, making early identification crucial (Benegas Urteaga et al., 2022). According to 2022 clinical practice guidelines for IPF and progressive pulmonary fibrosis jointly issued by ATS/ERS/JRS/ALAT, diagnosis of IPF typically integrates clinical symptoms, imaging studies (particularly high-resolution computed tomography, HRCT), pulmonary function tests, histological examinations (e.g., lung biopsy), and exclusion of other diseases. HRCT imaging and characteristic pulmonary function changes are key diagnostic criteria (Raghu et al., 2022). However, despite importance of HRCT in IPF diagnosis, its imaging changes remain incompletely understood (Yazaki et al., 2021), which limits early and accurate diagnosis. Therefore, exploring characteristics of IPF and developing novel diagnostic biomarkers are of paramount importance for improving diagnostic accuracy and clinical management.
DNA damage repair (DDR) is the cellular process that repairs DNA damage caused by internal and external environmental factors (e.g., reactive oxygen species, radiation, chemicals, oxidative stress). It involves multiple repair mechanisms, including direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and crosslink repair (De Bont and van Larebeke, 2004, Wang et al., 2023a, Sancar et al., 2004, Souliotis et al., 2019). These repair mechanisms are essential for maintaining genomic stability (Smith et al., 2021). Given that the lungs are directly exposed to external environment and often encounter harmful substances, they are particularly susceptible to DNA damage, which can impact lung health (Zhang et al., 2024). Typically, the body initiates a series of DNA repair mechanisms in response to DNA damage. However, if repair is insufficient or fails, damaged DNA may attack lung tissues, leading to pulmonary diseases such as IPF (Zhu et al., 2022), pulmonary hypertension (Sharma and Aldred, 2020), chronic obstructive pulmonary disease (COPD) (Sauler et al., 2018), and even lung cancer (Zhang et al., 2022). Thus, DDR plays a critical role in IPF pathogenesis. However, diagnostic value of DDR genes in IPF has not been fully explored. Therefore, investigating role of DDR in IPF is of great significance for understanding its pathogenesis and developing novel diagnostic approaches.
The present study aimed to identify DDR-related core genes involved in the progression of IPF and to assess their diagnostic potential and immunological associations. In this regard, we conducted a comprehensive analysis of multiple IPF transcriptomic datasets to characterize diagnostic value of DDR genes and determine their relationship with IPF immune microenvironment. We predicted several miRNAs that may regulate DDR genes. These findings hold important implications for early diagnosis and targeted progression of IPF.
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