Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular protection via induction of anti-inflammatory, antioxidant, and cyto-protective genes expression. Multiple studies have shown that activation or suppression of this transcriptional factor significantly affect progression of liver diseases. Comprehensive understanding the roles of Nrf2 activation/expression and the outcomes of its activators/inhibitors are indispensable for defining the mechanisms and therapeutic strategies against liver diseases. In this current review, we discussed recent advances in the function and principal mechanisms by regulating Nrf2 in liver diseases, including acute liver failure, hepatic ischemia–reperfusion injury (IRI), alcoholic liver disease (ALD), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC).

Background and Purpose-Ischemic postconditioning has been found to decrease brain infarct area and spinal cord ischemic injury. In this study, we tested the hypothesis that ischemic postconditioning reduces global cerebral ischemia/reperfusion-induced structural and functional injury in rats. Methods-Ten-minute global ischemia was induced by 4-vessel occlusion in male Sprague-Dawley rats.

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Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the b-catenin gene that lead to constitutive activation of the Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of six paired HB tumors and their corresponding lymphocytes. This identified 24 somatic nonsynonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP, KLHL22, TRPC4AP, and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain-of-functional mutations, and the CAPRIN2 (R968H/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the b-catenin in 42 HB tumors. We further used short hairpin RNA (shRNA)-mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that one novel oncogene (CAPRIN2) and three tumor suppressors (SPOP, OR5I1, and CDC20B) influence HB cell growth. Moreover, we found that SPOP S119N is a loss-of-function mutation in HB cells. We finally demonstrated that one of the mechanisms by which SPOP inhibits HB cell proliferation is through regulating CDKN2B expression. Conclusion: These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis.

Heat shock transcription factor 1 (HSF1) has been implicated in the differential regulation of cell stress and disease states. β-catenin activation is essential for immune homeostasis. However, little is known about the role of macrophage HSF1-β-catenin signaling in the regulation of NLRP3 inflammasome activation during ischemia and reperfusion injury (IRI) in the liver. This study investigated the functions and molecular mechanisms by which HSF1-β-catenin signaling influenced the NLRP3-mediated innate immune response in vivo and in vitro. Using a mouse model of IR-induced liver inflammatory injury, we found that mice with a myeloid specific HSF1 knockout (HSF1M-KO) displayed exacerbated liver damage based on their increased serum ALT levels, intrahepatic macrophage/neutrophil trafficking, and pro-inflammatory IL-1β levels compared to the HSF1-proficient (HSF1FL/FL) controls. Disruption of myeloid HSF1 markedly increased transcription factor X-box-binding protein (XBP1), NLRP3 and cleaved caspase-1 expression, which was accompanied by reduced β-catenin activity. Knockdown of XBP1 in HSF1-deficient livers using a XBP1 siRNA ameliorated hepatocellular functions and reduced the NLRP3/cleaved caspase-1 and IL-1β protein levels. In parallel in vitro studies, HSF1 overexpression increased β-catenin (Ser552) phosphorylation and decreased reactive oxygen species (ROS) production in bone marrow-derived macrophages. However, myeloid HSF1 ablation inhibited β-catenin but promoted XBP1. Furthermore, myeloid β-catenin deletion increased XBP1 mRNA splicing, whereas a CRISPR/Cas9-mediated XBP1 knockout diminished NLRP3/caspase-1. Conclusions: The myeloid HSF1-β-catenin axis controlled NLRP3 activation by modulating the XBP1 signaling pathway. HSF1 activation promoted β-catenin, which in turn inhibited XBP1, leading to NLRP3 inactivation and reduced IR-induced liver injury. Our findings demonstrated that HSF1-β-catenin signaling is a novel regulator of innate immunity in liver inflammatory injury and implied the therapeutic potential for the management of sterile liver inflammation in transplant recipients.

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Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. E2F1 activity is regulated by proteolysis mediated by the ubiquitin–proteasome system. However, the deubiquitylase that controls E2F1 ubiquitylation and stability remains undefined. Here we demonstrate that the deubiquitylase POH1 stabilizes E2F1 protein through binding to and deubiquitylating E2F1. Conditional knockout of Poh1 alleles results in reduced E2F1 expression in primary mouse liver cells. The POH1-mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Importantly, human hepatocellular carcinomas (HCCs) recapitulate POH1 regulation of E2F1 expression, as nuclear abundance of POH1 is increased in HCCs and correlates with E2F1 overexpression and tumour growth. Thus, our study suggests that the hyperactivated POH1–E2F1 regulation may contribute to the development of liver cancer.

m6A RNA modification is implicated in multiple cellular responses. However, its function in the innate immune cells is poorly understood. Here, we identified major m6A “writers” as the top candidate genes regulating macrophage activation by LPS in an RNA binding protein focused CRISPR screening. We have confirmed that Mettl3-deficient macrophages exhibited reduced TNF-α production upon LPS stimulation in vitro. Consistently, Mettl3flox/flox;Lyzm-Cre mice displayed increased susceptibility to bacterial infection and showed faster tumor growth. Mechanistically, the transcripts of the Irakm gene encoding a negative regulator of TLR4 signaling were highly decorated by m6A modification. METTL3 deficiency led to the loss of m6A modification on Irakm mRNA and slowed down its degradation, resulting in a higher level of IRAKM, which ultimately suppressed TLR signaling–mediated macrophage activation. Our findings demonstrate a previously unknown role for METTL3-mediated m6A modification in innate immune responses and implicate the m6A machinery as a potential cancer immunotherapy target.