Hepatocarcinogenesis Is Supported by Sublethal Necroptosis Signaling

Necroptosis, which is induced by activation of the necrosome that consists of RIPK1, RIPK3, and MLKL, has been shown to drive inflammation and hepatocellular carcinoma (HCC) development, but the manifestation of necroptosis and necroptosis responses in vivo as well as their role in cancer development are not well understood. Vucur and colleagues sought to determine both the mode of execution and the biologic responses after necroptosis pathway activation in vivo and showed that, in hepatocytes, a molecular switch exists that alternates between two modes of necroptosis signaling, which affects immune responses and subsequent hepatocarcinogenesis. Deletion of Traf2 and Casp8 in murine liver parenchymal cells (LPC^{ΔTraf2, Casp8}) induced massive inflammation, fibrosis, and liver parenchymal cell proliferation, which remodeled the hepatobiliary architecture, and LPC^{ΔTraf2, Casp8} mice also displayed multiple hepatic tumors. Crossing these LPC^{ΔTraf2, Casp8} mice with Ripk3^−/− mice revealed that the increase in hepatocarcinogenesis was due to RIPK1–RIPK3–MLKL-dependent necroptosis signaling activation. Moreover, hyperactivation of the NF-κB pathway was required to promote HCC development when necroptosis signaling was activated, and an NF-κB necroptosis gene signature was found to correlate with an unfavorable prognosis in patients with liver cancer. Mechanistically, NF-κB activation induces transcription of inflammatory cytokines and chemokines, including CCL20, with the necrosome facilitating the secretion of these inflammatory factors. Additionally, the release of these inflammatory factors upon NF-κB and necrosome activation led to the enrichment of clusters of profibrotic and protumor monocyte-derived macrophages that contribute to hepatocarcinogenesis. Finally, necroptotic hepatocytes with intact NF-κB signaling were found in a sublethal cell state, while those with inactive NF-κB signaling induced rapid necroptotic cell death and prevented inflammation and hepatocarcinogenesis. In summary, this study shows that, in vivo, necrosome activation in hepatocytes leads to distinct cell death fates that are dependent upon NF-κB activation status, which acts as a switch to either promote or prevent inflammation and hepatic carcinogenesis and suggests that pharmacologic targeting of necroptosis response pathways could be effective in blocking the carcinogenic potential of necroptosis signaling.

Vucur M, Ghallab A, Schneider AT, Adili A, Cheng M, Castoldi M, et al. Sublethal necroptosis signaling promotes inflammation and liver cancer. Immunity 2023;56:1578-95.e8.

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