Multi-omics analysis of liver molecular dysregulation leading to non-viral related hepatocellular carcinoma development

Chronic liver diseases exhibit diverse backgrounds, and it is believed that numerous factors contribute to progression to cancer. To achieve effective prevention of non-viral hepatocellular carcinoma, it is imperative to identify fundamental molecular abnormalities at the patient level. Utilizing cancer-adjacent liver tissues obtained from hepatocellular carcinoma patients (chronic liver disease), we conducted RNA-Seq and metabolome analyses. In the chronic liver disease cohort, upregulation of inflammation-associated signals was observed, concomitant with accumulation of acylcarnitine and fatty acid and depletion of NADP+, gamma-tocopherol, and dehydroisoandrosterone-3-sulfate-1 (DHEAS). To minimize heterogeneity, we performed multi-omics clustering, successfully categorizing the chronic liver disease cases into two distinct subtypes. Subtype 1 demonstrated elevated inflammatory levels, whereas Subtype 2 included a disproportionately high proportion of elderly cases. Furthermore, RNA-Seq analysis revealed upregulation of inflammatory signals in Subtype 1, while both subtypes exhibited downregulation of fatty acid metabolism. Metabolome analysis indicated a tendency of increased acylcarnitine levels in Subtype 1 and augmented fatty acid accumulation in Subtype 2. Validation of differentially expressed genes using the Gene Expression Omnibus (GEO) dataset revealed the potential for amelioration through supplementation with antioxidants such as epigallocatechin gallate (ECGC). Overall design: RNAseq analysis was performed using liver tissue adjacent to cancer from 56 patients with hepatocellular carcinoma (chronic liver disease) and liver tissue from 13 patients without hepatocellular carcinoma as controls.