HKUMed reveals that Resmetirom, a drug for treating metabolic dysfunction-associated fatty liver disease (MAFLD), has the potential to prevent and suppress liver cancer caused by fatty liver disease. The research is led by Professor Irene Ng Oi-lin (middle, front row).
A research team from the Department of Pathology, School of Clinical Medicine, LKS Faculty of Medicine of the University of Hong Kong (HKUMed), in collaboration with the HKU State Key Laboratory of Liver Research, has found that Resmetirom, a drug approved by the U.S. Food and Drug Administration (FDA) for treating metabolic dysfunction-associated fatty liver disease (MAFLD), demonstrates benefits beyond reducing liver fat and fibrosis. The study shows that the drug also has potential to prevent and suppress liver cancer caused by fatty liver disease. The findings were published in the international journal Hepatology. [link to the publication]
Link between fatty liver and liver cancer
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third leading cause of cancer-related death. With the rising prevalence of obesity, diabetes and metabolic syndrome, fatty liver and liver cancer caused by metabolic disorders, have become major contributors to the development of liver cancer. Published data indicate that approximately 3% of patients with fatty liver disease develop liver cancer each year, with a particularly high burden in Asia, where an estimated one-quarter of the population is impacted. Despite the availability of immune checkpoint inhibitors for advanced liver cancer, they show suboptimal efficacy in patients with fatty liver-related liver cancer, though the reasons remain unclear. This study aimed to investigate the underlying mechanisms and explore new therapeutic approaches for high-risk patients.
Midkine weakens the immune system
The HKUMed team developed a mouse model that closely resembles human fatty liver and MAFLD. Using single-cell RNA sequencing, the team analysed hundreds of thousands of liver and tumour cells at different stages of the disease, tracking changes in gene expression and cell signalling among hepatocytes, hepatic stellate cells and immune cells. The research found that the Midkine (MDK) gene and its receptor form an important cancer promoting pathway. MDK is a protein released by cells; when it binds to its receptor, it promotes tumour development by strengthening harmful signals between hepatic stellate cells and cancer-transforming hepatocytes. In patients with non-viral, non-alcoholic liver cancer, higher MDK levels correlate with an increased risk of cancer recurrence and shorter relapse-free survival.
Professor Irene Ng Oi-lin, Chair Professor at in the Department of Pathology, School of Clinical Medicine, HKUMed, who co-led the research, explained, 'Our findings show that MDK alters the normal functions of immune system through its receptor, impairing the body's ability to fight tumours. It affects macrophage activity, shifting its role from tumour-suppressive to tumour-promoting. Additionally, it causes T cells, which are normally responsible for destroying cancer cells, to progressively lose their function, leading to T-cell exhaustion and self-attack. This creates an environment that favours tumour growth and enables cancer cells to evade immune surveillance.'
Multiple benefits: Resmetirom reduces liver fat, improves metabolic health and modulates the tumour microenvironment
The team discovered that Resmetirom, an FDA-approved drug for fatty liver disease, significantly reduces liver fat and inhibits tumour growth in preclinical experiments. The treatment was also found to lower MDK levels. When combined with MDK inhibitors, the drug demonstrates a synergistic anti-cancer effect, further improving liver metabolism, reducing liver fat, suppressing tumours, and modulating the immune microenvironment. These findings show promising potential for future clinical applications.
Establishing a 'prevention-first' treatment model for high-risk patients
Professor Irene Ng emphasised that fatty liver-related liver cancer is not simply a result of excess fat but involves a cancer‑promoting signalling pathway driven by the MDK and its receptor. Targeting this pathway and modulating immune responses could improve treatment outcomes for patients who respond poorly to current immunotherapies.
She stated: 'By improving metabolic health and reducing the activity of this cancer-promoting pathway, Resmetirom provides a solid experimental basis for using a single drug to treat fatty liver and prevent liver cancer. Our next step is to validate relevant biomarkers in larger patient cohorts and collaborate with clinicians to design clinical trials that combine Resmetirom with immunotherapy and targeted therapy, ultimately establishing a prevention-oriented treatment approach for high-risk patients.'
About the Research Team
This study was co-led by Professor Irene Ng Oi-lin, Loke Yew Professor in Pathology and Chair Professor in the Department of Pathology, School of Clinical Medicine, HKUMed, and Director of State Key Laboratory of Liver Research at HKU; and Professor Daniel Ho Wai-Hung, Assistant Professor from the same department. The first authors are Postdoctoral Fellow Dr Vanilla Zhang Xin and PhD student Tina Suoangbaji.
