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

ABSTRACT: Tumor necrosis factor (TNF)-induced RIPK1-mediated cell death is implicated in various human diseases. However, the mechanisms RIPK1-mediated cell death is regulated by metabolic processes remain unclear. Here, we identify hexokinase 2 (HK2), a critical regulator of glycolysis, as a suppressor of TNF-induced RIPK1 kinase-dependent cell death through its non-metabolic function. HK2 inhibits RIPK1 kinase activity through constitutively phosphorylation at serine 32 of RIPK1. Inhibition of RIPK1 S32-phosphorylation results in RIPK1 kinase activation and subsequent cell death in response to TNFα stimulation. We further show that HK2 is elevated under pathological conditions including liver ischemia-reperfusion (IR) injury and hepatocellular carcinoma (HCC) via the transcriptional factor HMGA1.

SUBMITTER: Zou T 

PROVIDER: S-EPMC12615601 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature