Molecular Genealogy of Metabolic-associated Hepatocellular Carcinoma

Abstract

This review examines the latest epidemiological and molecular pathogenic findings of metabolic-associated hepatocellular carcinoma (HCC). Its increasing prevalence is a significant concern and reflects the growing burden of obesity and metabolic diseases, including metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, and type 2 diabetes. Metabolic-associated HCC has unique molecular abnormality and distinctive gene expression patterns implicating aberrations in bile acid, fatty acid metabolism, oxidative stress, and proinflammatory pathways. Furthermore, a notable frequency of single nucleotide polymorphisms in genes such as patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, and membrane-bound O-acyltransferase domain-containing 7 has been observed. The tumor immune microenvironment of metabolic-associated HCC is characterized by unique phenotypes of macrophages, neutrophils, and T lymphocytes. Additionally, the pathogenesis of metabolic-associated HCC is influenced by abnormal lipid metabolism, insulin resistance, and dysbiosis. In conclusion, deciphering the intricate interactions among metabolic processes, genetic predispositions, inflammatory responses, immune regulation, and microbial ecology is imperative for the development of novel therapeutic and preventative measures against metabolic-associated HCC.

Liver Diseases: Science, Fiction and the Foreseeable Future

“…Only very few studies into the genetic underpinnings of major liver diseases go back in time as far as a most recently published evolutionary investigation. Herein, a common variant-i.e., the risk allele PNPLA3 p.I148M (rs738409)-of the gene for patatinlike phospholipase domain-containing 3 (PNPLA3), which is prominently associated with an increased risk to develop steatotic liver disease, MASLD/NAFLD (including progressive inflammation), liver cirrhosis, and hepatocellular carcinoma [39], was studied. Contrary to non-human primates, this risk allele was identified in all Neanderthals and Denisovans, which indicates that the risk allele emerged prior to the split between the Neanderthals and modern humans.…”