Innovative RNA Therapy Targets Fatty Liver Disease

Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have developed a novel RNA-based therapy that could transform treatment for metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic fatty liver disease (NAFLD). This condition affects approximately 25% of the global population, and in its severe form, it can progress to cirrhosis or liver cancer. Currently, only two drugs have been approved by the US Food and Drug Administration (FDA) for MASH, which benefit just 30% of patients. These limitations highlight an urgent need for more effective therapies.

Introduction to the Research

Led by Assistant Professor Wang Jiong-Wei from the Department of Surgery, Cardiovascular Research Institute, and the Nanomedicine Translational Research Program (TRP) at NUS Medicine, the research team has created a revolutionary delivery system comprised of fat-like nanoparticles that can safely administer genetic drugs, specifically small interfering RNA (siRNA), directly to liver cells. This approach facilitates the silencing of a gene known as SPTLC2, responsible for producing ceramides, which have been identified as key drivers of liver fat accumulation, inflammation, and fibrosis.

Pathophysiology of Fatty Liver Disease

Fatty liver disease arises when excessive fat accumulates in liver cells, leading to inflammation (steatohepatitis) and can progress to severe complications such as:

• Cirrhosis
• Liver cancer
• End-stage liver disease

The overactivation of the SPTLC2 enzyme contributes to elevated ceramide levels in the liver, leading to increased fat storage and inflammation.

Mechanism of Action

Through the utilization of lipid nanoparticles carrying siRNA, the team observed significant changes in the liver's biochemical environment. By targeting SPTLC2, the following outcomes were recorded:

• Reduction in liver ceramide levels
• Decreased fat accumulation
• Improved liver inflammation and scarring
• Slower disease progression

Asst Prof. Wang noted, "Our study shows that shutting down harmful liver fats with RNA nanomedicines can significantly reduce liver fat, inflammation, and scarring. This identification of a clear molecular target in fatty liver disease reinforces the potential for liver-targeted RNA medicines to directly address underlying causative factors."

Potential Implications and Broader Applications

This pioneering research signifies the potential for RNA nanomedicines to revolutionize treatment modalities for fatty liver disease and potentially other metabolic disorders. Importance of ceramides extends beyond liver disease, with implications for conditions such as heart disease, obesity, and diabetes. The research team envisions the application of this therapy in varied contexts where elevated ceramide levels pose health risks.

“This breakthrough in liver-targeted RNA therapy opens up a new frontier that could complement existing care and make a meaningful difference for more patients.” – Dr. Mark Muthiah, Senior Consultant, Division of Gastroenterology and Hepatology

Future Directions and Conclusion

The team is focused on enhancing the durability of the therapy, aiming to minimize dosing frequency and initiating long-term safety studies. Plans for further exploration into other conditions exacerbated by ceramides include:

• Diabetes
• Cardiovascular disease

This innovative RNA therapeutic approach, leveraging lipid nanoparticle technology that gained prominence through COVID-19 vaccine development, showcases significant potential in combating chronic diseases such as fatty liver. The overall objective is to advance toward human clinical trials, thus broadening the spectrum of effective treatments for ceramide-related disorders.

References

Xiaodong Yu et al. Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH, Science Advances (2025). DOI: 10.1126/sciadv.adx2681

For further details, visit: Phys.org.