Exploiting gender-based biomarkers and drug targets: advancing personalized therapeutic strategies in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a high-incidence, poor-prognosis malignancy worldwide, requiring new strategies for treatment. Ubiquitination, especially ubiquitination through E3 ubiquitin ligases, plays an indispensable role in the development and progression of HCC. E3 ubiquitin ligases are crucial enzymes in ubiquitination, controlling the degradation of specific substrate proteins and influencing various cellular functions, such as tumor cell proliferation, apoptosis, migration, and immune evasion. In this review, we systematically summarize the mechanisms of E3 ubiquitin ligases in HCC, with a focus on the significance of RING, HECT, and RBR types in HCC progression. The review also looks at the potential for targeting E3 ligases to modulate the tumor microenvironment (TME) and increase immunotherapy efficacy. Future studies will optimize HCC treatment by formulating specific inhibitors or approaches that will be based on gene therapy targeting E3 ligases in order to overcome resistance issues with present treatments and create optimism in the journey of treatment for HCC patients.

Role and therapeutic potential of E3s in the tumor microenvironment of hepatocellular carcinoma

Wang,

Li,

Tang

et al. 2024

Extracellular vesicles in hepatocellular carcinoma: unraveling immunological mechanisms for enhanced diagnosis and overcoming drug resistance

Su,

Yue,

Yan

et al. 2024

Current research is focused on utilizing EVs as a biopsy tool to improve the diagnostic accuracy of HCC, reduce surgical risk, and explore their potential in modulating drug resistance and advancing immunotherapeutic strategies. Extracellular vesicles (EVs) have been increasingly recognized as important non-invasive biomarkers in hepatocellular carcinoma (HCC) due to the presence of a variety of biomolecules within them, such as proteins and RNAs, etc. EVs play a key role in the early detection, diagnosis, treatment, and prognostic monitoring of HCC. These vesicles influence the development of HCC and therapeutic response in a variety of ways, including influencing the tumor microenvironment, modulating drug resistance, and participating in immune regulatory mechanisms. In addition, specific molecules such as miRNAs and specific proteins in EVs are regarded as potential markers for monitoring treatment response and recurrence of HCC, which have certain research space and development prospects. In this paper, we summarize the aspects of EVs as HCC diagnostic and drug resistance markers, and also discuss the questions that may be faced in the development of EVs as markers.

Integrating multi-omics techniques and in vitro experiments reveals that GLRX3 regulates the immune microenvironment and promotes hepatocellular carcinoma cell proliferation and invasion through iron metabolism pathways

Li,

Chen,

Zhang

et al. 2024

BackgroundHepatocellular carcinoma (HCC) is a common malignancy worldwide, and its development is closely related to abnormalities in iron metabolism. This study aims to systematically analyze changes in iron metabolism in the tumor microenvironment of HCC using single-cell sequencing technology, and investigate the potential mechanisms by which iron metabolism regulation affects the survival of liver cancer patients.Materials and methodsSingle-cell sequencing data from hepatocellular carcinoma patients were obtained from the GEO database. By iron metabolism genomic scoring, we assessed differences in iron metabolism levels in hepatocellular carcinoma samples. By cell communication analysis as well as GO and KEGG enrichment analysis, we determined the functional role of iron metabolism in different cell types. We used survival analysis and Kaplan-Meier curves to assess the impact of iron metabolism levels on patient prognosis. In addition, we identified and analyzed the expression profile of the GLRX3 gene, investigated its key regulatory role in iron metabolism, and validated its clinical value as a prognostic marker. Finally, we explored the effect of GLRX3 on hepatocellular carcinoma phenotype by in vitro experiments such as PCR, transwell, CCK8, and wound healing assay.ResultsBioinformatics results and experimental validation confirmed the dysregulation of iron metabolism in the development of hepatocellular carcinoma, revealing iron’s regulatory influence across various cell types. Additionally, GLRX3 was identified as a key regulatory factor in iron metabolism, and the mechanism by which GLRX3 regulates tumor cell proliferation and immune evasion was determined. Furthermore, experiments verified GLRX3’s role in facilitating tumor cell proliferation and invasion.ConclusionThis study highlights the critical role of iron metabolism in the progression of hepatocellular carcinoma, particularly the regulatory mechanism of the GLRX3 gene in tumor cell proliferation and immune evasion. Iron metabolism abnormalities are not only drivers of liver cancer development but also key indicators of patient prognosis.