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NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition

Anna Juliane Vesting1, Alexander Jais2, Paul Klemm1

  • 1Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

Molecular Metabolism
|November 10, 2022
PubMed
Abstract

Insights

Nonalcoholic fatty liver disease (NAFLD) progression to liver cancer involves NIK, a kinase that inhibits protective JAK2/STAT5 signaling. Targeting NIK may offer new therapies for NASH and HCC.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • Nonalcoholic fatty liver disease (NAFLD) encompasses steatosis and nonalcoholic steatohepatitis (NASH), potentially progressing to hepatocellular carcinoma (HCC).
  • Inflammatory signaling, regulated by NFκB, is crucial in NASH and HCC pathogenesis.
  • The precise mechanisms driving NASH and HCC progression remain largely undefined.

Purpose of the Study:

  • To investigate the role of non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, the transition from NASH to HCC, and diethylnitrosamine (DEN)-induced HCC.
  • To elucidate NIK's mechanism of action in liver disease progression, independent of canonical NFκB pathways.

Main Methods:

  • Dietary and chemical interventions were performed in mice.
  • Analyses included single nucleus sequencing, gene expression, and histochemical methods.
  • Findings from mouse models were validated using human patient samples.

Main Results:

  • Hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis.
  • NIK's effects were independent of its role in the NFκB pathway.
  • Hepatic NIK was found to attenuate the hepatoprotective JAK2/STAT5 signaling pathway, which is essential for NASH and HCC progression in both mice and humans.

Conclusions:

  • NIK plays a critical role in NASH and HCC progression by inhibiting JAK2/STAT5 signaling.
  • NIK-mediated inhibitory JAK2 phosphorylation at serine 633 presents a potential therapeutic target for NASH and HCC.
  • Targeting NIK may offer novel therapeutic strategies for patients with liver disease.
Keywords:
NIK in NASH to HCC progressionNIK-Mediated JAK2 inhibition impairs STAT5 signaling

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