Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

Proceedings of the National Academy of Sciences of the United States of America
Shuixia TanJunying Yuan

Abstract

Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1 ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1 ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest...Continue Reading

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Citations

Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Shuixia TanJunying Yuan
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Chaoran SongJae Youl Cho
Apr 29, 2021·Journal of Hepatocellular Carcinoma·Gao LiuJi-Wei Xu
May 8, 2021·Cellular and Molecular Gastroenterology and Hepatology·Shunjie XiaXiujun Cai
Aug 12, 2021·Journal of Viral Hepatitis·Lauren E BallEric G Meissner

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