ArticleJCI insight2021
E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- Metabolic reprogramming in fibrosis-related diseases: underlying mechanisms and therapeutics.Molecular biomedicine · 2026Review
- Article
- Mechanisms of fibrotic tissue remodelling: insights from systemic sclerosis.Nature reviews. Rheumatology · 2026Review
- Regulation of basal and tumour necrosis factor α-induced fibroblast gene expression by peptidylarginine deiminase 2.The Journal of physiology · 2026Article
- Comparison of the Transcriptomic Signatures of Skin and Lung Fibroblasts from Patients with Systemic Sclerosis.Fibrosis (Hong Kong, China) · 2026Article
- An international perspective on the future of systemic sclerosis research.Nature reviews. Rheumatology · 2025Review
- P4HB regulates the TGFβ/SMAD3 signaling pathway through PRMT1 to participate in high glucose-induced epithelial-mesenchymal transition and fibrosis of renal tubular epithelial cells.BMC nephrology · 2024Article
- IGF-II regulates lysyl oxidase propeptide and mediates its effects in part via basic helix-loop-helix E40.Matrix biology : journal of the International Society for Matrix Biology · 2024Article
- Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis.Respiratory research · 2023Article
- The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches.Basic research in cardiology · 2023Review
- Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways.Biomolecules · 2023Review
- Is the Urokinase Plasminogen Activator/Plasminogen Activator Inhibitor-1 Ratio a Marker of Sonographic Septations in Pleural Infection?American journal of respiratory and critical care medicine · 2023Article
- Reduced Cathepsin L expression and secretion into the extracellular milieu contribute to lung fibrosis in systemic sclerosis.Rheumatology (Oxford, England) · 2023Article
- The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis.International journal of molecular sciences · 2023Review
- The versatile role of Serpina3c in physiological and pathological processes: a review of recent studies.Frontiers in endocrinology · 2023Review
- Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants.Biomedicines · 2022Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Fibroproliferative disorders such as systemic sclerosis (SSc) have no effective therapies and result in significant morbidity and mortality. We recently demonstrated that the C-terminal domain of endostatin, known as E4, prevented and reversed both dermal and pulmonary fibrosis. Our goal was to identify the mechanism by which E4 abrogates fibrosis and its cell surface binding partner(s). Our findings show that E4 activated the urokinase pathway and increased the urokinase plasminogen activator (uPA) to type 1 plasminogen activator inhibitor (PAI-1) ratio. In addition, E4 substantially increased MMP-1 and MMP-3 expression and activity. In vivo, E4 reversed bleomycin induction of PAI-1 and increased uPA activity. In patients with SSc, the uPA/PAI-1 ratio was decreased in both lung tissues and pulmonary fibroblasts compared with normal donors. Proteins bound to biotinylated-E4 were identified as enolase-1 (ENO) and uPA receptor (uPAR). The antifibrotic effects of E4 required uPAR. Further, ENO mediated the fibrotic effects of TGF-β1 and exerted TGF-β1-independent fibrotic effects. Our findings suggest that the antifibrotic effect of E4 is mediated, in part, by regulation of the urokinase pathway and induction of MMP-1 and MMP-3 levels and activity in a uPAR-dependent manner, thus promoting extracellular matrix degradation. Further, our findings identify a moonlighting function for the glycolytic enzyme ENO in fibrosis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.