Molecular mechanisms of MASHNASH-related hepatocellular carcinoma

Division Of Basic Sciences - Nci

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Abstract

We searched for genetic alleles among the 24 most significant alleles associated with body fat distribution from a genome-wide association study of 344,369 individuals and validated the top allele in three independent cohorts of American and European patients (N=1380) with MAFLD/MASH/HCC. We identified the rs3747579-TT variant, which was significantly associated with MASH-related HCC and demonstrated that rs3747579 is an expression quantitative trait locus (eQTL) of a mitochondrial DnaJ Heat Shock Protein Family (Hsp40) Member A3 (DNAJA3). We also found significant interactions between the rs3747579-TT variant and a previously identified PNPLA3 variant, both of which are functional variants contributing to the risk of MASH/HCC. Patients with HCC carrying the rs3747579-TT variant exhibited reduced expression of DNAJA3 and had an unfavorable prognosis. Furthermore, mice with hepatocyte-specific Dnaja3 depletion developed NASH-dependent HCC either spontaneously under a normal diet or enhanced by diethylnitrosamine. Dnaja3-deficient mice developed NASH/HCC characterized by significant mitochondrial dysfunction, which was accompanied by excessive lipid accumulation and inflammatory responses. The molecular features of MASH/HCC in the Dnaja3-deficient mice closely resembled those observed in human MASH/HCC. Therefore, we uncovered the genetic basis of DNAJA3 as a key player in MASH-related hepatocellular carcinoma (HCC). We are currently exploring the genetic interaction between DNAJA3 and TP53 in driving both MASH and MASH-related HCC.