Fidaxomicin Reduces Collagen Expression in Intestinal Fibroblasts Via Platelet-Derived Growth Factor Receptor Beta and Glycogen Synthase Kinase-3 Beta Inhibition

Sophie Irwin; Mieke van Daelen; Isabella Almaraz; Rebecca Park; Becca Nelson; Swapna Mahurkar-Joshi; Florian Rieder; David Q Shih; Wendy Ho; Berkeley Limketkai; Hon Wai Koon

doi:10.1053/j.gastro.2025.04.028

Fidaxomicin Reduces Collagen Expression in Intestinal Fibroblasts Via Platelet-Derived Growth Factor Receptor Beta and Glycogen Synthase Kinase-3 Beta Inhibition

Gastroenterology. 2025 May 19:S0016-5085(25)00765-6. doi: 10.1053/j.gastro.2025.04.028. Online ahead of print.

Authors

Affiliations

¹ Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
² Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Goodman-Luskin Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, California.
³ Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases Institute, Department of Inflammation and Immunity, Lerner Research Institute Program for Global Translational Inflammatory Bowel Diseases, Cleveland Clinic Foundation, Cleveland, Ohio.
⁴ F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
⁵ Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California. Electronic address: hkoon@mednet.ucla.edu.

PMID: 40398622
DOI: 10.1053/j.gastro.2025.04.028

Abstract

Introduction: About 30%-50% of patients with Crohn's disease (CD) eventually develop intestinal strictures, with intestinal fibrosis being a major component of them. There is currently no approved medication to treat fibrotic strictures.

Methods: 10X Genomics Visium spatial RNA sequencing and high-throughput screening were used to discover the molecular targets of intestinal fibrosis. Stricturing Crohn's disease (CDS) patient-derived primary human intestinal fibroblasts (CD-HIFs), stricturing Crohn's disease patient-derived serum exosomes (CDSE), fresh surgically resected whole-thickness ileal tissues, and mouse models of intestinal fibrosis were used.

Results: Spatial RNA sequencing found overexpression of platelet-derived growth factor receptor beta (PDGFRB) in the fibrotic ileal tissues of CDS patients. PDGFRB siRNA inhibited collagen expression in the CDSE-treated CD-HIFs. High-throughput screening identified PDGFRB inhibitors that suppressed collagen promoter activity in CDSE-treated CD-HIFs. A machine learning algorithm and molecular docking predicted PDGFR as a target for fidaxomicin. Fidaxomicin, a Food and Drug Administration-approved drug for Cdifficile infection, inhibited collagen and PDGFRB messenger RNA (mRNA) expression in CDSE-treated CD-HIFs and CDS patient-derived ileal tissues. CDSE-treated CD-HIFs had increased PDGFRb and glycogen synthase kinase-3 alpha/beta (GSK3a/b) phosphorylation. Fidaxomicin inhibited PDGFRb phosphorylation, PDGFRB mRNA expression, and GSK3b phosphorylation in CDSE-treated CD-HIFs. The antifibrogenic effect of fidaxomicin was attenuated by platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor 1, which are a PDGFRb ligand and a GSK3a/b phosphorylation activator, respectively. In the SAMP1/YitFc mice, oral fidaxomicin treatment inhibited ileal fibrosis and ileal PDGFRB mRNA expression and PDGFRb and GSK3b phosphorylation, which were abolished by Pdgfrb and Gsk3b overexpression.

Conclusions: Fidaxomicin inhibits intestinal fibrosis by reducing PDGFRb phosphorylation and expression, GSK3b phosphorylation, and collagen expression in intestinal fibroblasts.

Keywords: Fibrosis; High-Throughput Screening; Protein Array; Receptor; Spatial RNA Sequencing.