Fibrosing lung diseases (also referred to as “interstitial lung diseases”, ILD, or “diffuse parenchymal lung diseases”, DPLD) are rare pulmonary disorders characterized by a wide range of triggering factors (such as dust exposure, radiation, acute inflammatory, rheumatic, drug-related, or idiopathic causes), a heterogeneous clinical course, and in many cases progressive scarring of the lung. Affected patients initially experience shortness of breath during physical exertion and/or a persistent dry cough. As the disease progresses, dyspnea worsens and may eventually occur even at rest. Patients’ daily activity becomes increasingly restricted, and in the end stage only minimal exertion is possible. Most patients ultimately die from the consequences of lung fibrosis, often due to acute exacerbations that require hospitalization.
A prototypical ILD is idiopathic pulmonary fibrosis (IPF), which is relatively common among ILDs, follows a highly aggressive course, and is most likely caused by excessive programmed cell death of alveolar epithelial type II cells (AEC2)—the epithelial lining cells of the alveoli. This process appears to be partly genetically determined and partly triggered by exposure to harmful environmental factors. Over the past decade, three antifibrotic drugs (nintedanib, pirfenidone, and most recently nerandomilast) have been successfully evaluated in clinical studies for this disease. However, these medications are unable to completely halt disease progression, meaning that lung transplantation remains the only curative option for selected patients.
These diseases have been intensively studied for many years at the Center for Interstitial and Rare Lung Diseases at the Justus-Liebig-Universität Gießen. Andreas Günther, Professor of Medicine and scientific lead of the DPLD disease area at the German Center for Lung Research (DZL), and DZL scientist Poornima Mahavadi are the senior authors of an international study published in the journal Signal Transduction and Targeted Therapy. The study was conducted as part of the doctoral research of Bhavika Brahmanand Katariya in collaboration with other DZL colleagues from the UGMLC and BREATH sites.
The study investigated the role of an RNA-binding protein called “Fused in Sarcoma” (FUS) in lung fibrosis. FUS binds RNA and influences its stability as well as the activity of signaling pathways encoded by this RNA. The Giessen researchers found that cytoplasmic levels of FUS are significantly increased in patients with IPF. In lung fibroblasts, overexpression of FUS enhanced fibrotic responses, whereas knockdown of the gene suppressed them—particularly the proliferation of fibroblasts, the connective tissue cells responsible for scar formation. The effects of the two approved antifibrotic drugs, nintedanib and pirfenidone, also appear to be at least partly dependent on FUS.
Using state-of-the-art genome-wide analysis methods (CLIP-seq), the researchers identified the RNA molecules bound by FUS in IPF lung fibroblasts and the signaling pathways regulated by them. Many of these pathways are known to be involved in fibrotic processes, including those related to collagen production and TGF-β signaling.
By using the antisense oligonucleotide ION363, which is currently under clinical investigation in patients with amyotrophic lateral sclerosis (ALS), the researchers were able to therapeutically suppress FUS levels and reduce profibrotic signaling pathways both in IPF fibroblasts and in living IPF lung tissue cultured in 3D models known as high precision cut lung slices (PCLS). Interestingly, downregulation of FUS also induced the re-establishment of physiological metabolic processes and functions in alveolar epithelial type II cells (AEC2), particularly the normalization of the synthesis of surfactant—a surface-active lipoprotein complex essential for normal breathing under physiological pressure conditions in the thoracic cavity. Finally, the researchers demonstrated that ION363-mediated downregulation of FUS improved the regenerative capacity of the alveolar epithelium, as shown in an in vitro organoid assay (alveolosphere assay) using isolated AEC2 from IPF patients.
According to Prof. Günther, the results published in the Nature portfolio journal are of outstanding importance. For the first time, a therapeutic concept has been successfully established in preclinical models that is not only antifibrotic but also epithelial-protective and regenerative. Dr. Mahavadi adds that the consistent use of human cultured lung tissue and isolated cells from IPF patients—as performed in this study—raises hope that the translation of such preclinical findings to patients will improve, and that more clinical trials may succeed in the future than has been the case so far.
Original publication: Katariya BB, Chillappagari S, Arnold L. Targeting fused in sarcoma (FUS): a novel antisense strategy for treating idiopathic pulmonary fibrosis. Signal Transduct Target Ther. 2026 Feb 26;11(1):70. doi: 10.1038/s41392-026-02585-9. PMID: 41741410; PMCID: PMC12936215.
