Hepatocellular Carcinoma Mechanisms and Treatment Strategies

Hepatocellular carcinoma (HCC) arises against a backdrop of chronic liver injury, most commonly driven by viral hepatitis, metabolic syndrome and cirrhosis. Aberrant activation of signalling pathways—such as Wnt/β-catenin, PI3K/AKT and MAPK—supports malignant transformation through uncontrolled proliferation, evasion of apoptosis and altered cellular metabolism. Genetic and epigenetic alterations collaborate with a hostile tumour microenvironment (TME), characterised by hypoxia, stiffness and immune suppression, to promote tumour progression and resistance to therapy. Current curative options include surgical resection, liver transplantation and ablative therapies, but many patients present with advanced disease. Locoregional approaches such as transcatheter arterial chemoembolization (TACE) may extend survival in intermediate stages, while systemic treatments have evolved from multi-kinase inhibitors (sorafenib, lenvatinib) to second-line agents (regorafenib, cabozantinib) and immune checkpoint inhibitors. Emerging strategies emphasise personalised medicine, exploiting biomarkers of metabolism, immune profile and drug-metabolising enzymes, as well as advanced organotypic models to predict treatment response. Integrating mechanistic insights with novel delivery platforms and combination regimens aims to improve outcomes and reduce systemic toxicity.

Research from Nature Portfolio

Recent studies have illuminated the role of mitochondrial serine transport in non-viral HCC. Downregulation of the inner membrane transporter SFXN1 was found to attenuate lipid-induced cytotoxicity and reactive oxygen species production in HCC cells, leading to enhanced survival under high-fat conditions and poorer clinical outcomes. Loss of SFXN1 expression also correlated specifically with recurrence-free and overall survival in patients with metabolic liver disease, suggesting a context-dependent vulnerability that may guide targeted interventions in non-viral HCC.

Hepatocellular Carcinoma Mechanisms and Treatment Strategies publication trend

The graph below shows the total number of articles in hepatocellular carcinoma mechanisms and treatment strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Tumour microenvironment (TME): The cellular and molecular milieu surrounding cancer cells, including extracellular matrix, stromal cells, blood vessels, oxygen levels and immune components, which influences tumour behaviour and therapy response.

Cirrhosis: Advanced liver fibrosis characterised by nodular regeneration and scarring, leading to altered tissue stiffness, vascular architecture and increased risk of HCC.

Cytochrome P450 (CYP) enzymes: A family of haem-containing monooxygenases responsible for the oxidative metabolism of endogenous substrates and xenobiotics, including many chemotherapeutic agents.

Transcatheter arterial chemoembolization (TACE): A locoregional therapy involving delivery of chemotherapeutic agents and embolic particles into tumour-feeding arteries to induce ischaemia and enhance drug retention.

Reactive oxygen species (ROS): Chemically reactive oxygen-containing molecules, such as superoxide and hydrogen peroxide, that can induce cellular damage or mediate signalling pathways.

Serine transporter SFXN1: A mitochondrial inner membrane protein responsible for serine uptake into mitochondria, affecting lipid metabolism and redox homeostasis in HCC cells.

References

1. Vascularized Hepatocellular Carcinoma on a Chip to Control Chemoresistance through Cirrhosis, Inflammation and Metabolic Activity. Small Structures (2023).
2. Loss of SFXN1 mitigates lipotoxicity and predicts poor outcome in non-viral hepatocellular carcinoma. Scientific Reports (2023).
3. Tumor Microenvironment Alters Chemoresistance of Hepatocellular Carcinoma Through CYP3A4 Metabolic Activity. Frontiers in Oncology (2021).
4. CYP2E1 plays a suppressive role in hepatocellular carcinoma by regulating Wnt/Dvl2/β-catenin signaling. Journal of Translational Medicine (2022).