Disease Mechanisms and Therapeutic Advances in Idiopathic and Progressive Pulmonary Fibrosis: From Approved Drugs to Emerging Strategies

Interstitial lung diseases (ILDs) are frequently characterized by the presence of pulmonary fibrosis (PF), which may lead to respiratory failure secondary to irreversible parenchymal distortion. Although idiopathic pulmonary fibrosis (IPF) is the clinical prototype, the emergence of the progressive pulmonary fibrosis (PPF) phenotype has shifted the therapeutic paradigm toward shared pathogenic pathways while preserving the need to recognize the biological and clinical heterogeneity of the underlying ILDs. This state-of-the-art review integrates recent experimental and clinical data to provide a comprehensive overview of the transition from inflammatory models to the current epithelial-centric framework of fibrogenesis. In particular, the shift from ineffective anti-inflammatory strategies to the success of nintedanib and pirfenidone in both IPF and non-IPF progressive diseases is discussed. Furthermore, recent advances from phase II and III clinical trials targeting specific molecular drivers of fibrosis and vascular remodeling are analyzed, with a focus on pathway-oriented therapies, including nerandomilast, admilparant, and inhaled treprostinil. Understanding this molecular crosstalk is essential for the development of new therapeutic strategy based on precision medicine and it may support a new era of combination approaches aimed at stabilizing disease and improving patient outcomes in both idiopathic and progressive pulmonary fibrosis.