Sublethal necroptosis signaling promotes inflammation and liver cancer

Immunity. 2023 Jul 11;56(7):1578-1595.e8. doi: 10.1016/j.immuni.2023.05.017. Epub 2023 Jun 16.


It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Keywords: HCC; MLKL; NF-κB; RIP1; RIP3; RIPK1; RIPK3; TRAF2; intravital imaging; undead cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Humans
  • Inflammation / pathology
  • Liver Neoplasms*
  • NF-kappa B* / metabolism
  • Necroptosis
  • Protein Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism


  • NF-kappa B
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases