Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the primary cause of death in cancer cases, with significant public health concern worldwide. Despite the overall decline in the incidence and mortality rates of HCC in recent years in recent years, the emergence of metabolic liver disease-related HCC is causing heightened concern, especially in countries like the United States, the United Kingdom, and P.R. China. The escalation of metabolic liver disease-related HCC is attributed to a combination of factors, including genetic predisposition, lifestyle choices, and changes in the living environment. However, the pathogenesis of metabolic liver disease-associated HCC remains imperfect. In this review, we encapsulate the latest advances and essential aspects of the pathogenesis of metabolic liver disease-associated HCC, including alcoholic liver disease (ALD), metabolic dysfunction–associated steatotic liver disease (MASLD), and inherited metabolic liver diseases.

Keywords:

• hepatocellular carcinoma
• metabolic liver disease
• pathogenesis
• alcoholic liver disease
• metabolic dysfunction–associated steatotic liver disease

Abbreviations

HCC, hepatocellular carcinoma; ALD, alcoholic liver disease; MASLD, metabolic dysfunction–associated steatotic liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; AFL, alcoholic fatty liver; ASH, alcoholic steatohepatitis; CYP2E1, cytochrome P450 2E1; ROS, reactive oxygen species; 4-HNE, 4-hydroxynonenal; MDA, malondialdehyde; LPS, lipopolysaccharides; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TLR4, Toll-like receptor 4; MSLD, metabolic steatotic liver disease; MASH, metabolic dysfunction–associated steatohepatitis; T2DM, type 2 diabetes mellitus; IGF-1, insulin-like growth factor-1; IGF1R, insulin-like growth factor-1 receptor; IRS-1, insulin receptor substrate-1; GHR, growth hormone receptor; GH, growth hormone; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; AP-1, activator protein-1; NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; ER, endoplasmic reticulum; FAO, fatty acid oxidation; PPARα, peroxisome proliferator-activated receptor alpha; LPS, lipopolysaccharide; LAP3, leucine aminopeptidase 3; Thrap3, thyroid hormone receptor-associated protein 3; TRF-3001b, tRNA-derived fragment 3001b; TAK1, TGF-β-activated kinase 1; ECM, extracellular matrix; NAD⁺, nicotinamide adenine dinucleotide; mTOR, mechanistic target of rapamycin; AATF, apoptosis-antagonizing transcription factor; HH, hereditary hemochromatosis; AAT, Alpha 1 antitrypsin; HT1, hereditary tyrosinemia type 1; EpCAM, epithelial cell adhesion molecule; Pi, Protease inhibitor; FAH, fenugreek acyl acetate hydrolase; HSPs, heat shock proteins.

Acknowledgments

We acknowledge Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital for its administrative and technical support.

Author Contributions

All authors contributed significantly to the work reported, participated in drafting or writing, or substantially revising or critically reviewing the article; have agreed on the journal to which the article will be submitted; reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage; agree to take responsibility and be accountable for the contents of the article.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by: Shanxi Scholarship Council of China (Grant No. 2021-165). Shanxi Province Science Foundation for Distinguished Young Scholar (Grant No. 201901D211547). Science and research fund of Shanxi Health Commission (Grant No. 2019059, 2022042, 2022043). Shanxi Province “136 Revitalization Medical Project Construction Funds”. National Natural Science Foundation of China for Young Scholars (Grant No. 81201810). The doctor project of Shanxi Cancer Hospital, China (2017A06). Natural Science Foundation of Guangdong Province, China (2015A030313057).