Analysis of metabolic dysfunction-associated transcripts in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the primary form of liver cancer, because early symptoms may be absent, it is often detected late, resulting in a median survival of less than a year. Metabolically-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), has been identified as the fastest-growing cause of HCC globally, including in the United States. Vitellius et al. reported that MASLD may account for 35% of HCC cases. Furthermore, Younossi et al. mentioned it is estimated that by 2040, MASLD will be present in 55% of the population. Therefore, understanding the molecular mechanisms by which MASLD progresses to HCC is critical. In this study, we leveraged the existing whole-transcriptomic data from over 200 patients with MASLD or Metabolic Dysfunction-Associated Steatohepatitis (MASH) to identify all differentially expressed transcripts, compared to normal liver tissue. We examined the expression of unique noncoding transcripts that are associated with metabolism in HCC. To explore their potential functions, we used the Genomic Regions Enrichment of Annotations Tool (GREAT). Currently, we are employing various molecular and phenotypic based assays to identify their function in HCC. We will link their functions to HCC patient outcomes using RNA in situ hybridization in human tissues. The analysis identified differentially expressed transcripts in MASLD and MASH. We observed overlapping gene expression patterns across both conditions, along with distinct transcriptomic profiles unique to each stage. In MASLD, 4,403 genes were significantly upregulated and 4,411 downregulated compared to controls. Similarly, in MASH, 4,702 genes were upregulated and 4,433 downregulated. Comparative analyses revealed substantial overlap between the two cohorts, while also highlighting transcripts unique to each condition. These findings suggest that as metabolic liver disease progresses from fatty liver to steatohepatitis, many transcriptional alterations are conserved and become increasingly dysregulated. GREAT analyses indicate that these may be linked to various cellular processes known to play critical role in HCC, such as long-chain fatty-acyl-CoA and fatty-acyl-CoA metabolism, cellular catabolism, apoptosis, and kidney development, including mesonephros. Notably, many of these transcripts exhibit distinct expression patterns in HCC, suggesting their potential as diagnostic and therapeutic markers. We have begun elucidating their mechanism of action using loss- and gain-of approaches in HCC and how their expression is regulated in patient tissue samples.