. Author manuscript; available in PMC: 2025 Jun 13.

Published in final edited form as: Nat Rev Gastroenterol Hepatol. 2023 Mar 17;20(8):487–503. doi: 10.1038/s41575-023-00754-7

Table 2.

Molecular differences between NASH-HCC and other aetiologies

NASH-related HCC	HCC not related to NASH
Aetiology
Obesity, diabetes, metabolic syndrome	HBV infection, HCV infection, alcohol
~10% of HCCs globally; ~20% in Western countries	~90% of HCCs globally ~80% in Western countries
Male-to-female ratio 1.2:1	Male-to-female ratio 2–3:1
Molecular alterations
↑ ACVR2A and TP53 mutations
↑ MutSig-NASH-HCC	↑ MutSig24
↑ WNT/TGFβ proliferation	↓ WNT/TGFβ proliferation
SNPs in PNPLA3, TM6SF2, MBOAT7 and GCKR	SNPs in GTSM1 and GSTT1
Immune
Activation of dysfunctional immune cells, including CD8⁺PD1⁺ cells, IgA⁺ plasma cells, NK cells and T_H17 cells, that disrupt tumour immune surveillance	HBV: exhaustion of effector CD8⁺ T cells and infiltration of immunosuppressive T and B cells HCV: CD8⁺ T cell exhaustion and immune evasion by interference with MHC-I-dependent antigen presentation ALD: increased M2 macrophages and gMDSC infiltration
Microenvironment
↓ Underlying cirrhosis (60–70%)	↑ Underlying cirrhosis (>80%)
↑ Oxidative DNA damage, microbial signals generated by gut bacterial metabolism	Necroinflammation from chronic hepatitis viral exposure

ALD, alcohol-associated liver disease; gMDSC, granulocytic myeloid-derived suppressor cells; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; NK, natural killer; SNPs, single-nucleotide polymorphisms; TH, T helper. Data retrieved from refs. ^{3,5,13,14,22,101}.