Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Intense efforts have been made to elucidate the pathogeny, but the molecular mechanisms of HCC are still not well understood. To identify the candidate genes in the carcinogenesis and progression of HCC, microarray datasets GSE19665, GSE33006 and GSE41804 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape. A total of 273 DEGs were identified, consisting of 189 downregulated genes and 84 upregulated genes. The enriched functions and pathways of the DEGs include protein activation cascade, complement activation, carbohydrate binding, complement and coagulation cascades, mitotic cell cycle and oocyte meiosis. Sixteen hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell division, cell cycle and nuclear division. Survival analysis showed that BUB1, CDC20, KIF20A, RACGAP1 and CEP55 may be involved in the carcinogenesis, invasion or recurrence of HCC. In conclusion, DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the carcinogenesis and progression of HCC, and provide candidate targets for diagnosis and treatment of HCC.

Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1α stability and activating the HIF-1α signaling pathway. However, whether other metabolites regulate HIF-1α stability remains unclear. Here, we reported that deficiency of the enzyme in phenylalanine/tyrosine catabolism, glutathione S -transferase zeta 1 ( GSTZ1 ), led to accumulation of succinylacetone, which was structurally similar to α-ketoglutarate. Succinylacetone competed with α-ketoglutarate for prolyl hydroxylase domain 2 (PHD2) binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1α, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1α/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1α inhibitor combined with anti–programmed cell death ligand 1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1 -knockout mice, suggesting a potentially actionable strategy for HCC treatment.

To investigate whether the expression of triple motif protein 19/38 (TRIM19/38) mRNA in peripheral blood mononuclear cells (PBMCs) of HBeAg-negative chronic hepatitis B virus (HBV) carriers is associated with the response to pegylated interferon alpha (peg-IFN-α) treatment and HBsAg clearance. In this prospective study, HBeAg-negative chronic HBV carriers treated with peg-IFN-α completed 48 weeks of follow-up. After treatment with peg-IFN-α, the patients were divided into responders (R group) and nonresponders (NR group) according to the changes in HBV DNA and HBsAg levels at week 48 of treatment. According to whether serum HBsAg loss or seroconversion occurred, the patients were divided into a serological response group (SR group) and a nonserological response group (NSR group). The level of TRIM19/38 mRNA in PBMCs was detected by real-time fluorescence quantitative PCR. The diagnostic performance of TRIM19/38 was analysed by calculating the receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). 43 HBeAg-negative chronic HBV carriers, 35 untreated CHB patients and 19 healthy controls were enrolled in this study. We found that TRIM19/38 mRNA levels were significantly lower in untreated CHB patients than in healthy controls. In HBeAg-negative chronic HBV carriers who underwent prospective follow-up, TRIM19/38 mRNA levels were negatively correlated with HBV DNA and ALT at baseline. Among the patients treated with peg-IFN-α, 16 patients achieved a treatment response (R group) and 27 patients did not achieve a treatment response (NR group). Compared with baseline, HBsAg levels in the R group decreased significantly at 12 and 24 weeks of treatment; at the early stage of peg-IFN-α treatment, the dynamic changes in TRIM19/38 mRNA levels in the R and NR groups were different, and the TRIM19/38 mRNA levels in the R group were significantly higher than those in the NR group, especially at 24 weeks of treatment. ROC curve analysis showed that the changes in mRNA levels of TRIM19 and TRIM38 predicted the treatment response, with AUCs of 0.694 and 0.757, respectively. Among the patients treated with peg-IFN-α, 11 patients achieved a serological response (SR group) and 32 patients did not achieve a serological response (NSR group). Compared with baseline, HBsAg levels in the SR group decreased significantly at 12 and 24 weeks of treatment; TRIM19/38 mRNA levels were significantly higher in the SR group than in the NSR group at week 24. The higher level of TRIM19/38 mRNA in PBMCs of HBeAg-negative chronic HBV carriers may be related to the early treatment effect of peg-IFN-α and HBsAg clearance. TRIM19 and TRIM38 have clinical significance in predicting virological response and guiding treatment regimens.

The relationship between remnant cholesterol (RC) and homeostasis model assessment-insulin resistance (HOMA-IR) in the context of metabolic-associated fatty liver disease (MAFLD) remains an area of ambiguity. This investigation was designed to elucidate the potential association between RC and HOMA-IR in a cohort of American adults diagnosed with MAFLD. Data from 5533 participants were procured from the 2017–2018 US National Health and Nutrition Examination (NHANES) databases. A weighted linear regression model was employed to analyze the association between RC and HOMA-IR in the context of MAFLD. Preliminary analysis revealed that 44.67% of the participants were diagnosed with MAFLD, with a higher prevalence observed in individuals aged 50–64 years (31.84%, p < 0.0001) and in males compared to females (53.48% vs. 46.52%, p < 0.0001). A positive correlation was identified between RC and HOMA-IR in MAFLD patients. The threshold effect analysis model indicated a breakpoint at RC = 30 mg/dl, with a more pronounced positive correlation when RC < 30 mg/dl (β = 0.17, p < 0.001). Receiver operating characteristic analysis further demonstrated that among all lipid parameters, RC exhibited the largest area under the curve. The study findings suggest a positive correlation between RC and HOMA-IR in MAFLD patients, indicating that elevated RC may serve as an independent risk factor for MAFLD.