# Mechanism of Action of Anti-Fibrotic Peptide

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $373,750

## Abstract

ABSTRACT
Organ fibrosis is an irreversible endpoint of several diseases, leading to organ failure. Systemic sclerosis (SSc)
is a prototypic fibrotic disease with fibrosis affecting multiple organs including the lung. Currently the only
available therapeutic option for patients with fibrosis is organ transplantation, which is clinically impossible on
the scale necessary. The hallmark of fibrosis in multiple organs is the disruption of extracellular matrix (ECM)
homeostasis, resulting in accumulation of ECM components and subsequent organ failure. Fibrosis is
characterized by upregulation of fibrotic triggers such as connective tissue growth factor (CTGF), increase in
the deposition of collagen, fibronectin and other ECM components, enhanced matrix crosslinking due to an
increase in levels and activity of lysyl oxidase (LOX) enzyme, and decreased ECM degradation via reduced
matrix metalloprotease (MMP) levels and activity. We identified a peptide derived from the carboxy terminal
region of human endostatin, named E4, that exerts anti-fibrotic activity in vitro, ex vivo, and in vivo whether
administered prior to, concomitantly with, or following a fibrotic trigger such as bleomycin or TGFβ. Our recent
findings described in the preliminary studies suggest that E4 activates the urokinase pathway via increasing
urokinase plasminogen activator (uPA) levels and activity and decreasing those of its inhibitor PAI-1.
Mechanistically, E4 engages uPAR and phosphorylated β-catenin in fibroblast membranes. E4 also decreases
Egr-1 levels and increases nuclear levels of Pax6. We propose to 1) determine the role of β-catenin/E4 and
uPAR/E4 interactions in mediating the anti-fibrotic effects of E4, 2) define the role of phosphorylated β-catenin
and its reduced nuclear translocation in mediating the effects of E4, and 3) investigate the role of the
transcription factors Egr-1 and Pax6 downstream of E4. The beneficial effect of E4 in multiple pre-clinical
models of lung fibrosis emphasizes its relevance to human disease. Our goal is to advance mechanistic
knowledge of E4, which will allow for the identification of potential biomarkers and any possible side effects
while facilitating further improvement of the peptide as a therapy.

## Key facts

- **NIH application ID:** 9849305
- **Project number:** 5R01HL121262-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Carol A. Feghali-Bostwick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,750
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849305

## Citation

> US National Institutes of Health, RePORTER application 9849305, Mechanism of Action of Anti-Fibrotic Peptide (5R01HL121262-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849305. Licensed CC0.

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