Related Experiment Video

Updated: Jan 11, 2026

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System
08:15

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System

Published on: April 11, 2025

828

A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1

Tianhao Zou1, Ran Liu1, Gengqiao Wang1

  • 1Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Nature Communications
|November 13, 2025
PubMed

Insights

Hexokinase 2 (HK2) suppresses tumor necrosis factor (TNF)-induced RIPK1-mediated cell death via non-metabolic phosphorylation. Upregulating HK2 protects against liver injury and enhances cancer therapy, revealing a therapeutic target.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Metabolic regulation of disease

Background:

  • Tumor necrosis factor (TNF)-induced RIPK1-mediated cell death is crucial in human diseases.
  • The role of metabolic processes in regulating RIPK1-mediated cell death is not fully understood.

Purpose of the Study:

  • To investigate the non-metabolic function of hexokinase 2 (HK2) in regulating TNF-induced RIPK1 kinase-dependent cell death.
  • To explore the therapeutic potential of manipulating HK2 in pathological conditions.

Main Methods:

  • Investigated the interaction between HK2 and RIPK1 kinase activity.
  • Utilized cell culture models and animal models of liver ischemia-reperfusion (IR) injury and hepatocellular carcinoma (HCC).
  • Assessed the impact of HK2 modulation on cell death and therapeutic efficacy.

Main Results:

  • Identified HK2 as a suppressor of TNF-induced RIPK1 kinase-dependent cell death through non-metabolic phosphorylation of RIPK1 at serine 32.
  • Demonstrated that HK2 is upregulated by HMGA1 in liver IR injury and HCC.
  • Showed that elevated HK2 protects the liver from IR injury and that HK2 depletion in HCC enhances anti-cancer therapy.

Conclusions:

  • HK2's non-metabolic function is critical in suppressing RIPK1 kinase activity and preventing cell death.
  • HK2 represents a potential therapeutic target for RIPK1-related diseases, including liver injury and HCC.
  • Modulating HK2 offers a promising strategy to improve treatment efficacy in certain cancers.

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