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NF-кB determines the carcinogenic potential of necroptosis in liver

ABSTRACT: Background: Genetic inhibition of NF-кB in hepatocytes favors Caspase-8/3-dependent apoptosis driving hepatocellular carcinoma (HCC) development in mice, but NF-кB is hyper-active in most human HCCs. RIPK1-RIPK3-MLKL-dependent necroptosis represents an alternative form of programmed cell death (PCD). We show here that IкB-Kinase-(IKK)-dependent activation of NF-кB in hepatocytes induces a hyper-reactive form of cell-death responses towards necroptosis and thereby promotes hepatocarcinogenesis. This sequence is driven by NF-кB-dependent transcription of inflammatory and mitogenic cytokines like IL-6, MCP-1 and CCL20, which are released directly from necroptotic hepatocytes, serving as damage-associated-molecular-patterns (DAMPs) / alarmins to promote inflammation, hepatocyte- and oval-cell-proliferation, genetic alterations and hepatocarcinogenesis. In line, we identified an NF-кB-necroptosis-signature in human HCCs associated with an unfavorable patients' prognosis. In contrast, absence of NF-кB activation switches necroptosis towards a hypo-reactive, anti-carcinogenic form of cell-death. These results reveal that parenchymal NF-кB activation serves as an intracellular relay determining the reactivity and carcinogenic potential of PCD pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE80392 | GEO | 2026/06/01

REPOSITORIES: GEO

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