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, TGFbeta 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.
- Katariya, B. B.
- Chillappagari, S.
- Arnold, L.
- Guenther, S.
- Dasadia, Y.
- Noori, A.
- Krauss, E.
- Jiyani, T.
- Wrede, C.
- Hegermann, J.
- Bellusci, S.
- Fink, L.
- Ruppert, C.
- Muhlfeld, C.
- Benazzo, A.
- Hoetzenecker, K.
- Aigner, C.
- Guenther, A.
- Mahavadi, P.
