# The role of IL-17 signaling in alcohol-induced HCC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $464,520

## Abstract

ABSTRACT:
Hepatocellular carcinoma (HCC) is caused by hepatitis virus HBV/HCV, non-alcoholic steatohepatitis (NASH),
and alcoholic liver disease (ALD), which typically progress from liver fibrosis, to cirrhosis and cancer. Our
preliminary data demonstrate that genetic deletion of IL-17 signaling in steatotic hepatocytes significantly
attenuates the development of HCC in ALD-injured mice, suggesting that IL-17 signaling is a target for anti-
HCC therapy. Our central hypothesis is that IL-17 signaling regulates chemokine production, de novo
lipogenesis, and TNFRI expression/turnover in steatotic hepatocytes. IL-17 signaling promotes ALD- and
NASH-induced HCC via activation of TNF/TNFRI-SREBP1/2-DHCR7-cholesterol synthesis, and suppression
of ARTS-1/NUC2-dependent TNFRI exocytosis. The goal of the study is to characterize the mechanism by
which IL-17A/IL-17RA signaling regulates responses in metabolically injured hepatocytes, and to compare the
pathways of IL-17 signaling in the experimental models of ALD- and NASH. Strategy: Responses to IL-17
signaling will be compared side-by side in ALD- and NASH-injured WT and hepatocyte-specific IL-17RA
knockout mice with HCC. We determine if IL-17 signaling is similarly activated in NASH- and ALD-injured
hepatocytes. We determine if blocking of IL-17 signaling in steatotic hepatocytes is sufficient to suppress HCC
in the metabolically injured liver. Specifically, the role of IL-17 in the pathogenesis of DEN- or (Mup-uPA)-
induced HCC in ALD- and NASH-injury will be studied in WT and hepatocyte-specific IL-17RA knockout mice
(IL-17RAΔHep mice). Development of HCC, inflammation, steatosis and liver fibrosis will be across all groups of
mice. Mutagenesis of WT and IL-17RA-deficient AFP+YAP+ HCC, and responses of steatotic hepatocytes to
IL-17A will be characterized. Specifically, we determine if chemokine secretion, cholesterol synthesis are
suppressed in metabolically injured IL-17RA-deficient hepatocytes (AIM1). We will test a novel hypothesis by
which IL-17 signaling facilitates TNF/TNFRI-Caspase2-SP1-SREBP1/2-DHCR7-dependent cholesterol
synthesis in steatotic hepatocytes via blocking ARTS-1-NUCB2-regulated TNFRI exocytosis (and possibly IL-
6, IL-1RII) thereby prolonging TNF (IL-6, IL-1) signaling and promoting alcohol-induced HCC (AIM2). Our
findings will be translated into humans by characterization of IL-17RA-TNFRI-signaling pathways in archived
human livers from HCC patients with ALD. We will test if therapeutic blocking of the key IL-17 signaling
molecules (IL-17RA, TNFRI, ARTS-1, and DHCR7) specifically in hepatocytes using N-acetylgalactosamine
(GalNAc)-conjugated antisense RNA oligonucleotides (ASOs) can effectively suppress steatosis, fibrosis, and
HCC in WT mice with NASH and ALD (AIM3). If proven, hepatocyte-specific blocking of IL-17 signaling using
GalNAc-ASOs can provide a new strategy for HCC treatment in ALD and NASH patients.

## Key facts

- **NIH application ID:** 10852007
- **Project number:** 5R01AA028550-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** DAVID A. BRENNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,520
- **Award type:** 5
- **Project period:** 2021-08-06 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852007

## Citation

> US National Institutes of Health, RePORTER application 10852007, The role of IL-17 signaling in alcohol-induced HCC (5R01AA028550-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10852007. Licensed CC0.

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