The liver is a complicated heterogeneous organ composed of different cells. Parenchymal cells called hepatocytes and various nonparenchymal cells, including immune cells and stromal cells, are distributed in liver lobules with hepatic architecture. They interact with each other to compose the liver microenvironment and determine its characteristics. Although the liver microenvironment maintains liver homeostasis and function under healthy conditions, it also shows proinflammatory and profibrogenic characteristics that can induce the progression of hepatitis and hepatic fibrosis, eventually changing to a protumoral microenvironment that contributes to the development of hepatocellular carcinoma (HCC). According to recent studies, phosphatases are involved in liver diseases and HCC development by regulating protein phosphorylation in intracellular signaling pathways and changing the activities and characteristics of liver cells. Therefore, this review aims to highlight the importance of protein phosphatases in HCC development and in the regulation of the cellular components in the liver microenvironment and to show their significance as therapeutic targets.

CD8+ T cells play an important role in the elimination of tumors. However, the underlying mechanisms involved in eliciting and maintaining effector responses in CD8+ T cells remain to be elucidated. Pellino1 (Peli1) is a receptor signal-responsive ubiquitin E3 ligase, which acts as a critical mediator for innate immunity. Here, we found that the risk of developing tumors was dependent on Peli1 expression. Peli1 was upregulated in CD8+ T cells among tumor-infiltrating lymphocytes (TIL). In contrast, a deficit of Peli1 enhanced the maintenance and effector function of CD8+ TILs. The development of Peli1-deficient CD8+ TILs prevented T-cell exhaustion and retained the hyperactivated states of T cells to eliminate tumors. We also found that Peli1 directly interacted with protein kinase C-theta (PKCθ), a central kinase in T-cell receptor downstream signal transduction, but whose role in tumor immunology remains unknown. Peli1 inhibited the PKCθ pathway by lysine 48–mediated ubiquitination degradation in CD8+ TILs. In summary, the Peli1–PKCθ signaling axis is a common inhibitory mechanism that prevents antitumor CD8+ T-cell function, and thus targeting Peli1 may be a useful therapeutic strategy for improving cytotoxic T-cell activity.

Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT. Ssu72 is found to be highly expressed in BAT among adipose tissue depots, and the expression level of Ssu72 is increased upon acute cold exposure. Mice lacking adipocyte Ssu72 exhibit cold intolerance during acute cold exposure. Mechanistically, Ssu72 deficiency alters cytosolic mRNA translation program through hyperphosphorylation of eIF2α and reduces translation of mitochondrial oxidative phosphorylation (OXPHOS) subunits, resulting in mitochondrial dysfunction and defective thermogenesis in BAT. In addition, metabolic dysfunction in Ssu72-deficient BAT returns to almost normal after restoring Ssu72 expression. In summary, our findings demonstrate that cold-responsive Ssu72 phosphatase is involved in cytosolic translation of key thermogenic effectors via dephosphorylation of eIF2α in brown adipocytes, providing insights into metabolic benefits of Ssu72.

Growing evidence suggests a mechanistic link between steatohepatitis and hepatocellular carcinoma (HCC). However, the lack of representative animal models hampers efforts to understand pathophysiological mechanisms underlying steatohepatitis-related HCC. We found that liver-specific deletion of Ssu72 phosphatase in mice, leads to a high incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, but not HCC. However, loss of Ssu72 drastically increased the probability of HCC developing, as well as the population of hepatic progenitors, in various chemical and metabolic syndrome-induced HCC models. Importantly, hepatic Ssu72 loss resulted in the induction of mature hepatocyte-to-progenitor cell conversion, by dedifferentiation orchestrated by Ssu72-mediated hypo-phosphorylation of hepatocyte nuclear factor 4α (HNF4α), a master regulator of hepatocyte function. Our findings suggest that Ssu72-mediated HNF4α transcription contributes to the progression of steatohepatitis-associated HCC by regulating the dedifferentiation potential of hepatocytes. Thus, targeting the Ssu72-mediated HNF4α signaling that underlies the pathogenesis of steatohepatitis-associated HCC development could be a novel therapeutic intervention for steatohepatitis-associated HCC.

CD8+ T cells play an important role in the elimination of tumors. However, the underlying mechanisms involved in eliciting and maintaining effector responses in CD8+ T cells remain to be elucidated. Pellino1 (Peli1) is a receptor signal-responsive ubiquitin E3 ligase, which acts as a critical mediator for innate immunity. Here, we found that the risk of developing tumors was dependent on Peli1 expression. Peli1 was upregulated in CD8+ T cells among tumor-infiltrating lymphocytes (TIL). In contrast, a deficit of Peli1 enhanced the maintenance and effector function of CD8+ TILs. The development of Peli1-deficient CD8+ TILs prevented T-cell exhaustion and retained the hyperactivated states of T cells to eliminate tumors. We also found that Peli1 directly interacted with protein kinase C-theta (PKCθ), a central kinase in T-cell receptor downstream signal transduction, but whose role in tumor immunology remains unknown. Peli1 inhibited the PKCθ pathway by lysine 48–mediated ubiquitination degradation in CD8+ TILs. In summary, the Peli1–PKCθ signaling axis is a common inhibitory mechanism that prevents antitumor CD8+ T-cell function, and thus targeting Peli1 may be a useful therapeutic strategy for improving cytotoxic T-cell activity.

White adipose tissue (WAT) dysfunction under nutrient excess is a central driver of obesity and its related metabolic disorders. Maintaining precise regulation of adipogenesis and lipid metabolism in WAT is essential for systemic energy balance and metabolic health. Here, we identify Ssu72 phosphatase as a critical regulator of adipogenesis required for WAT expansion. Ssu72 expression is elevated in obese WAT. Notably, adipocyte-specific deletion of Ssu72 in mice confers resistance to high-fat diet (HFD)-induced obesity, accompanied by improved insulin sensitivity and altered energy expenditure. Ssu72 deficiency diminishes HFD-induced adipocyte hypertrophy and inflammation in WAT. Mechanistically, loss of Ssu72 inhibits PPARγ-mediated adipogenesis and lipid storage by hyperphosphorylation of GSK3β, resulting in suppression of WAT expansion. In addition, metabolic alterations in Ssu72-deleted WAT are reversed by restoring Ssu72 expression. Taken together, our findings reveal a novel adipocyte Ssu72-GSK3β axis that regulates obesogenic adipogenesis in white adipocytes, suggesting that Ssu72 is a promising target for controlling diet-induced obesity and whole-body metabolic homeostasis.