• biliary ductular reaction;
  • Caspase-8;
  • liver fibrosis;
  • MCP-1;
  • necroptosis


Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non-alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death—so far characterized as hepatocyte apoptosis—represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3-dependent “necroptosis” in NASH and NASH-induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase-8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun-(N)-terminal Kinase (JNK). Furthermore, RIP3-dependent JNK activation promotes the release of pro-inflammatory mediators like MCP-1, thereby attracting macrophages to the injured liver and further augmenting RIP3-dependent signaling, cell death, and liver fibrosis. Thus, RIP3-dependent necroptosis controls NASH-induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH.


Thumbnail image of graphical abstract

RIP3-dependent necroptosis mediates NASH-induced liver fibrosis via activation of JNK, MCP-1-mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. Caspase-8 appears to suppress the deleterious effect of RIP3.

  • RIP3 mediates liver injury in MCD-diet-induced NASH.
  • RIP3—similar to Caspase-8—does not affect CCl4-induced liver fibrosis and thus might be a specific target in metabolic liver disease.
  • Human NASH livers strongly express RIP3.
  • Targeting RIP3 might represent a novel-specific approach in human NASH.