# Targeting Acid Ceramidase for Hepatic Fibrogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $640,808

## Abstract

ABSTRACT
Fibrosis is the common endpoint responsible for liver failure in nearly every form of chronic liver disease, yet
there remains no effective treatment for preventing the progression of fibrosis. Our preclinical studies identified
a novel antifibrotic target, the enzyme acid ceramidase (aCDase). We demonstrated that depletion or inhibition
of aCDase reduces HSC activation, the key step in hepatic fibrogenesis. Moreover, pharmacologic inhibition of
aCDase or genetic knockout of aCDase in HSCs reduces fibrosis in mouse models for liver fibrosis as well as in
precision cut liver slices from fibrotic rats and humans. The long-term goal of this project is to develop a potent
inhibitor of aCDase for the treatment of hepatic fibrosis. Using structure-based drug design, we have recently
discovered a novel series of covalent inhibitors with increased potency and metabolic stability. The objective of
this application is to optimize this lead series towards the goal of oral, once-daily dosing for the treatment of
hepatic fibrosis. In Aim 1, we will use structure-informed medicinal chemistry approaches to identify a covalent
inhibitor based on the lead series with optimal potency, ADME profile, selectivity, and PK properties for oral
delivery. In Aim 2, we will use mouse and human models of fibrogenesis to demonstrate the efficacy of the
optimized compounds. We have assembled a team with expertise in hepatic fibrosis, medicinal chemistry, and
antifibrotic drug development. This work is the first to target the aCDase pathway for the treatment of hepatic
fibrogenesis. Our expected outcome is identification of a candidate compound that is ready for nomination for
IND-enabling studies. This work is highly significant because it will facilitate a new treatment strategy for patients
with hepatic fibrosis, for which no therapies currently exist.

## Key facts

- **NIH application ID:** 10777097
- **Project number:** 1R01DK137892-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Hyunil Jo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,808
- **Award type:** 1
- **Project period:** 2023-12-15 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10777097

## Citation

> US National Institutes of Health, RePORTER application 10777097, Targeting Acid Ceramidase for Hepatic Fibrogenesis (1R01DK137892-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10777097. Licensed CC0.

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