Genetic Determinants of Progressive Pulmonary Fibrosis: A Comprehensive Review

Progressive pulmonary fibrosis (PPF) encompasses fibrosing interstitial lung diseases marked by relentless scarring of the lungs, leading to respiratory failure. Although its pathogenesis remains incompletely understood, recent genetic discoveries have shed light on the molecular mechanisms that drive PPF onset and progression. This comprehensive review summarizes current knowledge of PPF genetics, highlighting both rare pathogenic variants and more common susceptibility polymorphisms. Key genetic contributors include telomere maintenance genes, surfactant protein genes, and the MUC5B promoter variant rs35705950, which is the strongest known genetic risk factor for idiopathic pulmonary fibrosis. We also discuss epigenetic factors such as DNA methylation and histone modifications that regulate fibrotic gene expression. Integrating genetic findings with clinical phenotypes reveals distinct disease endotypes with different prognoses and therapeutic responses, laying the groundwork for precision medicine in PPF treatment. Finally, we address the clinical implications of PPF genetics, including advances in genetic testing, biomarker development, and emerging gene-targeted treatment strategies.