Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality rates in patients with rheumatoid arthritis (RA). Currently, the treatment of RA-ILD remains highly challenging. This study aims to identify potential therapeutic targets for RA-ILD through a systematic druggable genome-wide Mendelian randomization (MR) analysis. We performed a genome-wide MR analysis by integrating expression quantitative trait loci (eQLT) of 6888 druggable genes and genetic summary statistics from a genome-wide association study of RA-ILD. A colocalization analysis was performed to prioritize genes strongly associated with RA-ILD. Enrichment analysis, protein-protein interaction network construction, drug prediction, and molecular docking were further conducted to provide valuable guidance for the development of targeted therapies. A total of 33 druggable genes showed significant association with RA-ILD, one of which, CISD1, was robustly validated through colocalization analysis. Notably, three key target genes-CST7, ATN1, and FCER2-were identified as potential mediators of the treatment effect of cyclophosphamide, a current clinical treatment for RA-ILD. This study employed MR and colocalization analysis to identify 33 potential drug-target genes for RA-ILD, including three genes associated with the mechanism of action of cyclophosphamide. These findings offer a promising roadmap for developing targeted therapies, potentially shifting treatment strategies from broad immunosuppression to precise molecular interventions.

HER2-mutant lung cancer represents approximately 2-5% of all NSCLCs and is associated with poor prognosis. Two different HER2-targeted therapeutic approaches with different mechanisms of action -antibody-drug conjugates (ADCs) and HER2-selective tyrosine-kinase inhibitors (TKIs)- have shown convincing efficacy in pretreated patients. Trastuzumab deruxtecan (T-DXd) was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in about 50% of these patients. Toxicity, while overall manageable, includes an increased risk of interstitial lung disease (ILD), which can be problematic and requires close clinical monitoring. More novel HER2-directed ADCs have confirmed the solid efficacy in this tumor type, showing variable rates of ILD as a class effect of these agents. On the other hand, novel orally available TKIs with higher specificity and inhibitory potency against HER2 over wild type EGFR such as sevabertinib (a dual HER2/EGFR mutant-selective reversible TKI) or zongertinib (an irreversible HER2-selective TKI that spares EGFR, including mutant EGFR) have further demonstrated deep and durable responses in this disease. Toxicities with these agents are mostly related to EGFR wild type inhibition, with significantly lower rates of ILD. Consistent with its selectivity and mechanism of action, zongertinib offers a favorable tolerability profile, with mainly low-grade adverse events including those related to wild type EGFR inhibition. In this review, we first describe the molecular landscape and clinical features of HER2-mutant NSCLC. Then, we summarize the clinical and preclinical evidence of HER2-targeted therapies and provide a forward-looking perspective of the treatment landscape of HER2-mutant NSCLC.

Idiopathic interstitial pneumonias (IIPs) represent a heterogeneous group of rare lung diseases characterized by distinct radiological and histological phenotypes. The new 2025 classification provides a more detailed definition of individual entities, including the incorporation of idiopathic eosinophilic pneumonias and rare forms, without yet altering current therapeutic approaches. The most common form is idiopathic pulmonary fibrosis (IPF), where antifibrotic therapy with pirfenidone and nintedanib has been shown to improve prognosis. Recent clinical trials (FIBRONEER, TETON) suggest further therapeutic options. The treatment of other IIPs, particularly nonspecific interstitial pneumonia (NSIP), is based on systemic corticosteroids and immunosuppressive therapy, though evidence remains limited. Complications such as pulmonary hypertension and acute exacerbations significantly impact disease course. Non-pharmacological strategies, including oxygen therapy, pulmonary rehabilitation, and, in selected cases, lung transplantation, play an important role.