Multiomics Analysis of Liver Molecular Dysregulation Leading to Nonviral-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 nonviral 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 multiomics 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) data set revealed the
potential for amelioration through supplementation with antioxidants
such as epigallocatechin gallate (EGCG).