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Project description: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 investigates the pathological role of FUS in IPF and assesses 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. Functional assays were performed on primary lung fibroblasts derived from healthy donors and IPF patients to assess the effects of FUS overexpression and knockdown. 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 using CLIP-Seq, and global transcriptional changes following FUS inhibition were analyzed via RNA sequencing. FUS overexpression in healthy fibroblasts promoted proliferation, while its 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 FUS binding to a distinct set of pro-fibrotic RNAs in IPF. ION363 treatment downregulated fibrotic gene programs, including those linked to ECM remodeling, TGF-β signaling, and epithelial dysfunction. On the contrary, ION363 promoted functional markers and improved morphology in patient derived 3D-alveolospheres. We conclude that FUS is a pivotal regulator of fibrotic signaling in IPF and targeting FUS via ASO represents a promising therapeutic avenue for IPF.
2026-01-26 | GSE310470 | GEO
Project description: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 investigates the pathological role of FUS in IPF and assesses 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. Functional assays were performed on primary lung fibroblasts derived from healthy donors and IPF patients to assess the effects of FUS overexpression and knockdown. 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 using CLIP-Seq, and global transcriptional changes following FUS inhibition were analyzed via RNA sequencing. FUS overexpression in healthy fibroblasts promoted proliferation, while its 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 FUS binding to a distinct set of pro-fibrotic RNAs in IPF. ION363 treatment downregulated fibrotic gene programs, including those linked to ECM remodeling, TGF-β signaling, and epithelial dysfunction. On the contrary, ION363 promoted functional markers and improved morphology in patient derived 3D-alveolospheres. We conclude that FUS is a pivotal regulator of fibrotic signaling in IPF and targeting FUS via ASO represents a promising therapeutic avenue for IPF.
2026-01-26 | GSE310475 | GEO
Project description: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 investigates the pathological role of FUS in IPF and assesses 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. Functional assays were performed on primary lung fibroblasts derived from healthy donors and IPF patients to assess the effects of FUS overexpression and knockdown. 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 using CLIP-Seq, and global transcriptional changes following FUS inhibition were analyzed via RNA sequencing. FUS overexpression in healthy fibroblasts promoted proliferation, while its 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 FUS binding to a distinct set of pro-fibrotic RNAs in IPF. ION363 treatment downregulated fibrotic gene programs, including those linked to ECM remodeling, TGF-β signaling, and epithelial dysfunction. On the contrary, ION363 promoted functional markers and improved morphology in patient derived 3D-alveolospheres. We conclude that FUS is a pivotal regulator of fibrotic signaling in IPF and targeting FUS via ASO represents a promising therapeutic avenue for IPF.
2026-01-26 | GSE310473 | GEO
Project description:Targeting Fused in Sarcoma (FUS): A Novel Antisense Strategy for Treating Idiopathic Pulmonary Fibrosis
| PRJNA1366387 | ENA
Project description:Targeting Fused in Sarcoma (FUS): A Novel Antisense Strategy for Treating Idiopathic Pulmonary Fibrosis [CLIP-Seq]
| PRJNA1366401 | ENA
Project description:Targeting Fused in Sarcoma (FUS): A Novel Antisense Strategy for Treating Idiopathic Pulmonary Fibrosis [RNA-Seq IPF]
| PRJNA1366400 | ENA
Project description:Targeting Fused in Sarcoma (FUS): A Novel Antisense Strategy for Treating Idiopathic Pulmonary Fibrosis [RNA-Seq PCLS]
| PRJNA1366403 | ENA
Project description:This is a time of substantial progress in the evaluation and care of patients with idiopathic pulmonary fibrosis (IPF). In addition to the approval and widespread availability of the first IPF-specific therapies, there have been improvements in imaging interpretation and lung biopsy methods to enable more expeditious and more accurate diagnosis. Recent advances in identifying genetic factors that underlie susceptibility to IPF and affect prognosis have raised the possibility of personalized therapeutic approaches in the future. Further, evolving work is elucidating novel mechanisms influencing epithelial, mesenchymal, and inflammatory cell responses during the injury-repair process, thus advancing understanding of disease pathogenesis. As analytic approaches mature, the field is now poised to harness the power of rapidly advancing "omics" technologies to further accelerate progress.
| S-EPMC6378692 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease characterized by progressive scarring of the lung tissue, leading to respiratory failure. There is no cure for IPF, and current anti-fibrotic treatments modestly arrest its further progression. IPF prevalence and incidence increase with age, which is a recognized risk factor. Intense clinical and basic research over the last fifteen years has shown that hallmarks of accelerated aging are present in the lungs of patients with IPF. Different cell types in IPF lungs exhibit premature hallmarks of aging, including telomere attrition and cellular senescence. In this Review, we discuss recent insights into the mechanisms behind these age-related alterations and their contribution to the development of lung fibrosis. We focus on the genetic and molecular basis of telomere attrition in alveolar type II epithelial cells, which promote cellular senescence and lung fibrosis. Mechanistically, senescent cells secrete pro-fibrotic factors that activate scar-forming myofibroblasts. Ultimately, senescent alveolar epithelial cells lose their regenerative capacity, impeding fibrosis resolution. In addition, mitochondrial dysfunction is strongly associated with the appearance of senescent epithelial cells and senescent myofibroblasts in IPF, which persist in the fibrotic tissue by adapting their metabolic pathways and becoming resistant to apoptosis. We discuss emerging novel therapeutic strategies to treat IPF by targeting cellular senescence with the so-called senotherapeutics.
| S-EPMC7913053 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Current evidence suggests that IPF may be initiated by repeated epithelial injuries in the distal lung, which are followed by abnormal wound healing responses that occur because of intrinsic and extrinsic factors. Mechanisms contributing to chronic damage of the alveolar epithelium in IPF include dysregulated cellular processes such as apoptosis, senescence, abnormal activation of the developmental pathways, aging, and genetic mutations. Therefore, targeting the regenerative capacity of the lung epithelium is an attractive approach in the development of novel therapies for IPF. Endogenous lung regeneration is a complex process involving coordinated cross-talk among multiple cell types and reestablishment of a normal extracellular matrix environment. This review will describe the current knowledge of reparative epithelial progenitor cells in the alveolar region of the lung and discuss potential novel therapeutic approaches for IPF, focusing on endogenous alveolar repair.
| S-EPMC8525210 | biostudies-literature