Mechanism of hepatitis C virus-mediated development and progression of liver cirrhosis and hepatocellular carcinoma

Abstract

Chronic infection with hepatitis C virus (HCV) can trigger chronic inflammation in the liver, which gradually progresses to liver fibrosis and cirrhosis, and ultimately increases the risk of hepatocellular carcinoma. However, the underlying molecular mechanisms and sex-specific regulatory pathways involved remain not fully elucidated. This article focuses on the analysis of the study published by Groover et al. This study concentrates on the expression characteristics of estrogen receptor (ER) subtypes (ERα, ERβ) and tumor necrosis factor-alpha in the liver, and explores the impact of sex-based relative expression differences of these molecules on the pathogenic mechanism of HCV. Based on this study, this article proposes future research directions to provide references for in-depth analysis of the mechanism underlying HCV-mediated development and progression of liver cirrhosis and hepatocellular carcinoma, as well as for promoting the development of sex-specific prevention and treatment strategies.

Key Words: Hepatitis C virus; Liver cirrhosis; Hepatocellular carcinoma; Estrogen receptor; Tumor necrosis factor-alpha; Sex difference

Core Tip: The study by Groover et al is the first to systematically analyze the expression differences and sex-specific correlations of estrogen receptor subtypes and tumor necrosis factor-alpha in the livers of healthy individuals and patients with hepatitis C virus (HCV)-related liver diseases. The study confirms that the expression changes of estrogen receptor β and tumor necrosis factor-alpha are important factors involved in HCV-mediated progression of liver cirrhosis and hepatocellular carcinoma, and sex-specific molecular regulation may be a key mechanism underlying the prognostic differences of HCV-related diseases.

TO THE EDITOR

We have read the original research titled “Sex based relative expression of estrogen receptors and tumor necrosis factor-alpha in liver affects hepatitis C virus viral pathogenesis” by Groover et al[1]. Taking the sex difference in the prognosis of hepatitis C virus (HCV) infection as its core starting point, this study deeply explores the impact of the expression correlation between estrogen receptor (ER) subtypes and tumor necrosis factor-alpha (TNF-α) in the liver on the pathogenic mechanism of HCV. Its research design and findings are highly consistent with the current research hotspots in the fields of “inflammation-tumor axis regulation”[2,3] and “sex differences in disease progression”[4], providing a new perspective for analyzing the molecular mechanisms of HCV-mediated liver cirrhosis and hepatocellular carcinoma (HCC), and thus possessing important scientific value and clinical reference significance.

The core contributions of this study are mainly reflected in three aspects: Firstly, it is the first to clarify the dominant expression characteristic of ERβ in the liver of healthy individuals, and this expression advantage is consistent across both sexes. Secondly, it establishes an inverse expression correlation between ERβ and TNF-α in HCV-related diseases. Thirdly, it reveals the sex specificity of the interaction between ER subtypes and their correlation with TNF-α. These findings not only provide a molecular explanation for the clinical phenomenon that “HCV disease progresses faster in men and postmenopausal women”, but also construct a new hypothesis of the “ER-inflammation” regulatory axis, pointing out the direction for subsequent research.

However, this study still has limitations that need to be further addressed in subsequent research. Firstly, the representativeness and size of the samples are insufficient. Affected by the epidemiological characteristics of HCV-related liver cancer, only 5 female patients were included in the HCV/HCC group of the study. The excessively small sample size may reduce the statistical power of the subgroup analysis for females. At the same time, the study population is mainly composed of American individuals, lacking data from populations in other regions such as Asia and Africa, which limits the generalizability of the conclusions and makes it difficult to extend to HCV-infected populations of different ethnicities worldwide. Secondly, the coverage of disease stages is incomplete. The study only included patients with end-stage liver diseases (HCV/cirrhosis, HCV/HCC), and did not include samples from stages such as chronic HCV infection and early liver fibrosis. Therefore, it is impossible to construct a dynamic change trajectory of “ER subtypes-TNF-α” throughout the course of HCV-related diseases, making it difficult to clarify whether the two are “driving factors” or “accompanying results” of disease progression, and unable to accurately locate key regulatory nodes. Thirdly, the depth of mechanism exploration is insufficient. The study mainly relies on correlation analysis, and does not verify the direct regulatory effect of ERβ on TNF-α or the specific molecular pathways through in vitro cell models or in vivo animal models. Moreover, it did not detect the isomers of ER subtypes (such as ERα46, ERα36)[5-7]. Previous studies have confirmed that these isomers may play a pro-carcinogenic role in liver cancer, and the neglect of these isomers in this study may lead to the omission of key regulatory molecules, affecting the integrity of the conclusions. Fourthly, the control of clinical variables is not comprehensive. The study did not include clinical information such as the patients’ history of hormone replacement therapy, complicated metabolic diseases (such as non-alcoholic fatty liver disease), and drinking history. However, these factors may interfere with the research results by affecting ER expression or TNF-α inflammatory levels, increasing the potential bias of the conclusions[8].

In conclusion, the study by Groover et al[1] has made valuable contributions to linking sex-specific molecular expression with the pathogenesis of HCV, laying a foundation for mechanism research and the development of therapeutic targets for HCV-related liver diseases. In the future, functional determination, prospective cohort studies, and multi-omics analysis should be carried out, and clinical variables and genetic polymorphism data should be integrated to construct a “genetics-sex-hormone-inflammation” multi-dimensional regulatory network, so as to clarify the regulatory mechanism of ERβ on TNF-α and its impact on the progression of HCV-related diseases. It is expected that subsequent studies can break through the existing limitations, analyze the relevant mechanisms in depth, and provide new targets and theoretical support for the sex-specific prevention and treatment of HCV-mediated liver cirrhosis and HCC.