FUS Plays a Role in Lung Fibroblast Activation

Fused in sarcoma (FUS) is a DNA/RNA-binding protein which has been implicated in circular RNA biogenesis, genomic integrity, and regulation of gene expression. Research has indicated that FUS contributes to the progression of tissue fibrosis, including fibrosis in the kidney, heart, and liver. However, the involvement of FUS in lung fibrosis is still unclear. Idiopathic Pulmonary Fibrosis (IPF) is a deadly fibrotic interstitial lung disease which mostly affects the aged. This illness significantly affects the patient’s quality of life, has poor prognosis due to diagnostic challenges and lack effective treatments. Abnormal activation of pulmonary fibroblasts and increase in myofibroblast population is one of the prominent pathogenic mechanisms identified in lung fibrosis. In this study, we investigated the role of FUS in lung fibroblast activation and other possible mechanisms. Genotype tissue expression (GTEx) database revealed that FUS is a widely expressed protein in various organs including lungs. Single cell RNA sequencing dataset showed that FUS was upregulated in fibroblasts and myofibroblasts of IPF lungs compared to those of healthy lungs. FUS was confirmed to be a nuclear protein in human pulmonary fibroblast (HPFs) using western blot and immunofluorescence. Profibrotic cytokine Transforming Growth Factor- β1 (TGFβ1) treatment of HPFs did not change the nuclear localization or mRNA levels of FUS. Knockdown of FUS in HPFs led to a significant reduction in the expression of fibroblast activation markers including α-smooth muscle actin (α-SMA), fibronectin and type 1 Collagen A1 (COL1A1). As FUS engages in circular RNA biogenesis, we examined the effect of FUS knockdown on circCOL1A1 expression. We observed that the relative expression of circCOL1A1 in HPFs was adversely impacted by the knockdown of FUS. CircCOL1A1 silencing suppressed TGFβ1-induced HPF activation as demonstrated by the decreased expression of α-SMA and COL1A1. Our results suggest that FUS is a pro-fibrotic gene that activates pulmonary fibroblasts likely by promoting circCOL1A1 biogenesis. R01HL157450; P30GM149368 This abstract was presented at the American Physiology Summit 2025 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.