ASK1/p38 axis inhibition blocks the release of mitochondrial “danger signals” from hepatocytes and suppresses progression to cirrhosis and liver cancer

Author:

Peng Zhenwei12,Wei Guangyan12,Huang Pinzhu2,Matta Heansika2,Gao Wen2,An Ping2,Zhao Shuangshuang2,Lin Yi2,Tan Li23,Vaid Kahini2,Skelton-Badlani Disha2,Nasser Imad4,Budas Grant5,Lopez David5,Li Li5,Breckenridge David5,Myers Rob5,McHutchison John5,Kuang Ming36,Popov Yury V.2ORCID

Affiliation:

1. Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

2. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

3. Center of Hepatopbiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

4. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

5. Gilead Sciences, Inc., Foster City, California, USA

6. Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Abstract

Background and Aims: Apoptosis Signal–regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems. Approach and Results: Short-term (4–6 wk) and long-term (24–44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c.Mdr2−/− murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2/ model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21+ hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c.Mdr2−/− mice resulted in markedly reduced tumor number and size by ~50% compared to the control group. Conclusions: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/Mdr2 −/− mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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