FUS is Required for Wnt Protein Binding and Extracellular Matrix Production in Lung fibroblasts

Fused in Sarcoma (FUS) is an RNA binding protein present in nearly all major organs. This protein plays a key role in DNA repair, genome stability, transcriptional regulation, and alternative splicing. Several studies link FUS to neurodegenerative diseases, cancers, and fibrotic diseases. But its role in lung diseases, especially fibrotic lung diseases, is a vastly underexplored area. The activation and trans-differentiation of pulmonary fibroblasts into myofibroblasts is a vital mechanism which drives pulmonary fibrosis. We hypothesized that FUS is pro-fibrotic and contributes to pulmonary fibrosis by activating lung fibroblasts. In this study, we found that FUS was upregulated in IPF fibroblasts. Knockdown of FUS in human pulmonary fibroblasts (HPFs) using lentiviral short hairpin RNAs reduced transforming growth factor β1 (TGFβ1)-induced fibroblast activation. To investigate how FUS activates lung fibroblasts, we performed RNA sequencing on control and FUS-knockdown HPFs. Heat map and principal component analysis revealed a clear separation of control and FUS-knocked down samples, with or without TGFβ1 treatments, and samples clustered in accordance with their treatment conditions. While TGFβ1 upregulated 265 genes and downregulated 388 in control cells, it upregulated only 66 genes and downregulated 62 in the FUS-knockdown samples. The Gene Ontology (GO) enrichment analysis showed that FUS knockdown attenuated the TGFβ1-induced expression of genes associated with cell differentiation, cell migration, extracellular matrix organization, and Wnt protein binding. Key affected genes included NF1, JAM2, and MYADM, which are involved in cell differentiation and migration; ADAMTS, FBN2, MMP24, LUM, and MGP, which contribute to extracellular matrix regulation; and FZD7, FZD1, CTHRC1, and ROR1, which participate in Wnt protein binding. These findings suggest that FUS regulates fibroblast activation possibly through activating the Wnt pathway. Support or Funding Information: R01HL157450; P30GM149368 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.