Thursday, December 18, 2025 12/18/2025

Targeting Acid Ceramidase for Hepatic Fibrogenesis

Award Number: R01DK137892
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Targeting Acid Ceramidase for Hepatic Fibrogenesis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $697,010 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/16/2025	NON-COMPETING CONTINUATION	$697,010
														Subtotal = $697,010

Issue Date FY: 2025 ( Subtotal = $576,728 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/5/2024	NON-COMPETING CONTINUATION	$576,728
														Subtotal = $576,728

Issue Date FY: 2024 ( Subtotal = $640,808 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/12/2023	NEW	$640,808
														Subtotal = $640,808

Grand Total All Awards = $1,914,546

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Targeting Acid Ceramidase for Hepatic Fibrogenesis

Award Number: R01DK137892

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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