This study aimed to identify genetic risk factors driving the progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and then to hepatocellular carcinoma (HCC). Researchers focused on the most significant genetic alleles related to body fat distribution and identified an allele (rs3747579-TT) significantly associated with NASH-related HCC. The rs3747579 allele was found to influence the expression of DNAJA3, a mitochondrial protein, which was linked to poor prognosis in patients with NASH-related HCC. The study also highlighted interactions between this allele and the PNPLA3 variant in increasing the risk of NASH/HCC.

In experimental models, mice with hepatocyte-specific depletion of Dnaja3 developed NASH-dependent HCC, either spontaneously or when enhanced by a carcinogenic agent. These mice exhibited mitochondrial dysfunction, excessive lipid accumulation, and inflammatory responses, closely mirroring the molecular features of human NASH/HCC. The findings suggest that DNAJA3 plays a critical role in the development of NASH-related HCC, providing valuable insights into the genetic basis of the disease and potential therapeutic targets for managing its progression.

Reference: Chang CW, Chen YS, Huang CH, et al. A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma. Hepatology. 2025 Jan 1;81(1):60-76. doi: 10.1097/HEP.0000000000000637. Epub 2023 Oct 23. PMID: 37870291; PMCID: PMC11035488.