Targeting fused in sarcoma (FUS): a novel antisense strategy for treating idiopathic pulmonary fibrosis PMID: 41741410

ADC Targets in Oncology

2026-04-10

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.

Bhavika B Katariya ¹ , Shashipavan Chillappagari ¹ , Lisa Arnold ¹ ² , Stefan Guenther ³ , Yash Dasadia ¹ , Afshin Noori ¹ , Ekaterina Krauss ¹ ⁴ , Trushnali Jiyani ¹ , Christoph Wrede ⁵ ⁶ ⁷ , Jan Hegermann ⁵ ⁶ ⁷ , Saverio Bellusci ⁸ ⁹ ¹⁰ ¹¹ , Ludger Fink ¹² , Clemens Ruppert ¹ ⁹ , Christian Mühlfeld ⁵ ⁶ ⁷ , Alberto Benazzo ¹³ , Konrad Hoetzenecker ¹⁴ , Clemens Aigner ⁴ ¹³ , Andreas Guenther ¹ ⁴ ⁹ ¹⁰ ¹¹ ¹⁵ , Poornima Mahavadi ¹⁶ ¹⁷

Affiliations

1. Center for Interstitial and Rare Lung Diseases, Department of Internal Medicine, Justus-Liebig University (JLU), Giessen, Germany.
2. Department of Dermatology and Allergology, University Hospital Munich (LMU), München, Germany.
3. Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
4. European IPF Network and European IPF Registry, Giessen, Germany.
5. Hannover Medical School, Institute of Functional and Applied Anatomy, Hannover, Germany.
6. Hannover Medical School, Research Core Unit Electron Microscopy, Hannover, Germany.
7. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
8. Department of Internal Medicine, JLU, Giessen, Germany.
9. Universities of Giessen & Marburg Lung Center (UGMLC), Member of German Center for Lung Research (DZL), Giessen, Germany.
10. Cardio-Pulmonary Institute (CPI), JLU Giessen, Giessen, Germany.
11. Institute of Lung Health (ILH), JLU Giessen, Giessen, Germany.
12. Institute of Pathology, Dermatopathology, Cytology and Molecular Pathology, UEGP, Wetzlar, Germany.
13. Department of Thoracic Surgery, Vienna General Hospital, Vienna, Austria.
14. Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
15. Lung Clinic, Agaplesion Evangelisches Krankenhaus Mittelhessen, Giessen, Germany.
16. Center for Interstitial and Rare Lung Diseases, Department of Internal Medicine, Justus-Liebig University (JLU), Giessen, Germany. [email protected].
17. Universities of Giessen & Marburg Lung Center (UGMLC), Member of German Center for Lung Research (DZL), Giessen, Germany. [email protected].

Abstract

Fused in sarcoma (FUS) is a highly conserved RNA-binding protein with essential roles in RNA processing and genomic stability. While extensively studied in the context of neurodegeneration, its involvement in fibrotic diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unexplored. This study investigated the pathological role of FUS in IPF and assessed its viability as a therapeutic target. Specifically, we examine how FUS dysregulation contributes to fibrotic signaling and evaluate whether therapeutic silencing of FUS offers a rational strategy to modulate disease progression. To assess the effects of FUS overexpression and knockdown, functional assays were performed on primary lung fibroblasts derived from healthy donors and IPF patients. Precision-cut lung slices (PCLs) and 3D alveolosphere cultures from IPF patients were treated with a FUS-targeted antisense oligonucleotide (ASO;ION363). FUS-RNA interactions were mapped via CLIP-Seq, and global transcriptional changes following FUS inhibition were analyzed via RNA Sequencing. FUS overexpression in healthy fibroblasts promoted proliferation, whereas FUS knockdown attenuated the hyperproliferative phenotype in IPF fibroblasts. IPF cells demonstrated aberrant cytoplasmic mislocalization of FUS. Standard-of-care treatments (pirfenidone, nintedanib) reduced FUS expression in PCLs. CLIP-Seq revealed that FUS binds to a distinct set of profibrotic RNAs in IPF. ION363 treatment downregulated fibrotic gene programs, including those linked to ECM remodeling, TGFβ signaling, and epithelial dysfunction. In contrast, ION363 promoted functional marker expression and improved morphology in patient-derived 3D alveolospheres. We conclude that FUS is a pivotal regulator of fibrotic signaling in IPF and that targeting FUS via ASO represents a promising therapeutic avenue for IPF.