Abstract

Simple SummaryNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is an increasing factor in the cause of hepatocellular carcinoma (HCC). The incidence of NAFLD has increased in recent decades, accompanied by an increase in the prevalence of other metabolic diseases, such as obesity and type 2 diabetes. However, current treatment options are limited. Both genetic factors and non-genetic factors impact the initiation and progression of NAFLD-related HCC. The early diagnosis of liver cancer predicts curative treatment and longer survival. Some key molecules play pivotal roles in the initiation and progression of NAFLD-related HCC, which can be targeted to impede HCC development. In this review, we summarize some key factors and important molecules in NAFLD-related HCC development, the latest progress in HCC diagnosis and treatment options, and some current clinical trials for NAFLD treatment.Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

Highlights

  • Licensee MDPI, Basel, Switzerland.Primary liver cancer was the sixth most commonly diagnosed and the third most common cause of cancer-related death worldwide in 2020 [1]

  • The expression of more than 3000 long non-coding RNAs (lncRNAs) was observed to be changed in the liver tissues of db/db mice fed with a nonalcoholic whereas steatohepatitis (NASH) diet, and the expression of 381 lncRNAs was significantly increased during nonalcoholic fatty liver disease (NAFLD) progression to NASH [39]

  • Another study showed that aberrant expression of four key RNA-binding proteins (RBPs), including mitochondrial ribosomal protein L54 (MRPL54), enhancer of zeste homolog 2 (EZH2), PPARγ coactivator 1 alpha (PPARGC1A), and eukaryotic translation initiation factor 2-alpha kinase 4 (EIF2AK4), can be applied to Hepatocellular carcinoma (HCC) prognosis [100]

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Summary

Introduction

C > T in PDCD1 gene increased the progression of NAFLD-HCC compared to the wildtype C allele. A meta-analysis study showed that the rs58542926 T allele in TM6SF2 gene had a significant association with HCC development compared to the C allele [27]. This effect may be mediated by regulating the cell cycle [28]. The rs641738 C > T variant, near two genes encoding membrane-bound Oacyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4), was shown to be associated with the progression of NAFLD and liver fibrosis [31]. More evidence is needed to support the role of the rs641738 variant of MBOAT7/TMC4 in the susceptibility of NAFLD and NAFLD-related HCC progression

Epigenetic Factors
DNA Methylation
Long Non-Coding RNAs
MicroRNAs
E2F1 and E2F2
SREBP-1
Post-Transcriptional Modification
RNA Splicing Factor
RNA-Binding Proteins
RNA Editing
Potential Diagnosis of NAFLD-Related HCC
Treatment Options against HCC
Systemic Therapies and Immunotherapy
CAR T Cells
Peptides
Treatment against NAFLD
Treatment against Liver Fibrosis
Findings
Conclusions
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