# Promotion of fatty liver disease by the ASK1 pathway

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $548,418

## Abstract

Project Summary
Human obesity represents a serious world-wide health problem that is associated with metabolic syndrome
and the development of non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic
steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). The estimated prevalence of NAFLD
in the USA is approximately 25% of the population (1). Estimates for the prevalence of NASH are confounded
by the limited availability of reliable non-invasive methods for diagnosis, but approximately 25% of patients with
NAFLD exhibit NASH (1). The development of scarring (cirrhosis) and hepatic fibrosis contributes to the
development of HCC, the most common liver cancer and the 3rd leading cause of cancer-related death in the
USA (2, 3).
The high incidence of NAFLD/NASH represents a major health problem because: 1) NASH is anticipated to
become the leading indication for liver transplantation (4); and 2) NAFLD/NASH-associated HCC is the primary
cause of obesity-related cancer death in the USA (4). Lifestyle interventions, including dietary calorie
restriction and exercise, are key aspects of current therapy. However, there is an unmet need for effective
pharmacotherapy. Several medications are currently under development, including approaches to reduce
steatosis, correct intestinal dysbiosis, promote oxidative stress defense, and suppress fibrosis (5, 6).
Recent studies have established that the oxidative stress-responsive protein kinase ASK1 (a member of the
MAP3K group) is a promising drug target for the treatment of NASH (5, 6). The small molecule Selonsertib is a
potent inhibitor of ASK1 protein kinase activity that causes reduced NASH-related hepatic fibrosis (7, 8), a key
determinant of disease progression (4). Successful phase 2 trials of Selonsertib in NASH patients (7, 8) have
led to phase 3 trials (STELLAR 3 and STELLAR 4) that are currently in progress (8).
The mechanism that accounts for the beneficial effects of blocking ASK1 is unknown, but likely involves a
reduction in the activation state of down-stream signaling pathways (e.g. stress-activated MAPK). ASK1 is
expressed ubiquitously. Consequently, no information is available concerning the hepatic cell type that
mediates the ASK1-promoted hallmarks of NASH, including hepatic fibrosis. It is possible that ASK1 plays a
key role in an inflammatory response (e.g. in Kupffer cells and other immune cells) that drives hepatic fibrosis
(9). Alternatively, ASK1 may play an important role in steatotic hepatocytes that promotes fibrosis (10). It is
also possible that the key role of ASK1 may be in stellate cells that are directly involved in hepatic fibrosis (11).
The relevant hepatic cell type that mediates the essential function of ASK1 in NASH has therefore not been
defined. Moreover, the mechanism that mediates ASK1 regulation during the development of NASH is not
understood.
This proposal is designed to identify the mechanism of ASK1 signaling during NASH developmen...

## Key facts

- **NIH application ID:** 10224186
- **Project number:** 5R01DK121545-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Roger J. Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $548,418
- **Award type:** 5
- **Project period:** 2019-09-20 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224186

## Citation

> US National Institutes of Health, RePORTER application 10224186, Promotion of fatty liver disease by the ASK1 pathway (5R01DK121545-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10224186. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*