Principal Investigator: Sayed Obaidullah Aseem, Ph.D., M.D.
Institution: Virginia Commonwealth University
Reporting Period: 5/22/2024 – 5/22/2025
Grant Title: The transcription factor RUNX1 is pivotal in TGFβ-activated cholangiocyte signaling with the immune system in primary sclerosing cholangitis
Study Objective: The primary objective of the study was to elucidate the role of the protein RUNX1 in the pathogenesis of PSC.
Summary of Progress and Key Findings:
- Inhibition of RUNX1 significantly reduced the secretion of various proinflammatory cytokines.
- Transforming Growth Factor-β (TGF-β), a master regulator of fibrosis, enhances RUNX1 activity, thereby linking RUNX1 directly to the fibrotic processes in the liver.
- Studies conducted in mouse models of PSC revealed that either genetic ablation or pharmacological inhibition of RUNX1 significantly attenuated liver fibrosis, thereby providing compelling evidence for the pivotal role of RUNX1 in the development of fibrosis characteristic of PSC.
- Aramchol —a drug with a well-established safety record from clinical trials that targets fat metabolism—shows promise in reducing fibrosis, suggesting a potential downstream therapeutic avenue related to the RUNX1 pathway.
- By employing advanced spatial transcriptomics to analyze archived liver samples from PSC patients who underwent liver transplantation helped identify that larger ducts exhibited signs of activated cancer-related pathways; however, at this end-stage of PSC, the inflammatory and fibrotic signals appeared “exhausted”, and therefore, no change was detected in the RUNX1 related pathway.
