Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD-HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD-HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.

This study aimed to investigate the effect and underlying mechanism of lncRNA CASC2 in malignant melanoma (MM). Expression of CASC2 in MM tissues and cells were detected. A375 cells were transfected with pc-CASC2, si-CASC2, miR-18a-5p inhibitor or corresponding controls, and then cell proliferation, migration and invasion were detected using MTT assay, colony formation assay, and Transwell analysis, respectively. The relationship of miR-18a-5p and CASC2 or RUNX1 was detected by luciferase reporter assay. Compared with normal skin tissues or cells, the levels of CASC2 and RUNX1 were significantly reduced, while miR-18a-5p level was obviously increased in MM tissues (all p < 0.01). Cell viability, colony number, migration and invasion were significantly decreased in cells with pc-CASC2 compared with cells with pcDNA3.1 (all p < 0.05), meanwhile, these effects were consistent with cells with miR-18a-5p inhibitor. Then, the luciferase reporter assay revealed that CASC2 acted as a molecular sponge for miR-18a-5p and RUNX1 was a target gene of miR-18a-5p. Moreover, CASC2 overexpression promoted the expression of RUNX1, while upregulated miR-18a-5p significantly reversed the effect of CASC2 on RUNX1 level (all p < 0.05). Upregulated CASC2 may inhibit cell proliferation, migration and invasion through regulating miR-18a-5p and its target gene RUNX1 in MM.

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Sepsis is a life-threatening condition with limited therapeutic options, characterized as excessive systemic inflammation and multiple organ failure. Macrophages play critical roles in sepsis pathogenesis. Metabolism orchestrates homeostasis of macrophages. However, the precise mechanism of macrophage metabolism during sepsis remains poorly elucidated. In this study, we identified the key role of zinc fingers and homeoboxes (Zhx2), a ubiquitous transcription factor, in macrophage glycolysis and sepsis by enhancing 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) expression. Mice with myeloid Zhx2-specific deletion (abbreviated as MKO) showed more resistance to cecal ligation and puncture and LPS-induced sepsis, exhibiting as prolonged survival, attenuated pulmonary injury, and reduced level of proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β. Interestingly, Zhx2 deletion conferred macrophage tolerance to LPS-induced glycolysis, accompanied by reduced proinflammatory cytokines and lactate. Consistently, treatment of glycolytic inhibitor 2-deoxyglucose almost completely abrogated the protection of mice from LPS-induced sepsis initiated by Zhx2 deletion in macrophages. RNA sequencing and chromatin immunoprecipitation assays confirmed that Zhx2 enhanced transcription of Pfkfb3, the glycolysis rate-limiting enzyme, via binding with Pfkfb3 promoter. Furthermore, Pfkfb3 overexpression not only rescued the reduction of macrophage glycolysis caused by Zhx2 deficiency, displaying as extracellular acidification rates and lactate production but also destroyed the resistance of mice to LPS-induced sepsis initiated by transfer of bone marrow–derived macrophages from MKO mice. These findings highlight the novel role of transcription factor Zhx2 in sepsis via regulating Pfkfb3 expression and reprogramming macrophage metabolism, which would shed new insights into the potential strategy to intervene sepsis.