The liver sits quietly at the centre of human metabolism, maintaining a delicate balance of sugars, fats, and toxins with remarkable precision. But when this balance begins to falter, the entire metabolic network starts to strain. Metabolic dysfunction–Associated Steatohepatitis (MASH) arises not as an abrupt illness, but as a slow, silent unravelling of metabolic harmony.

It begins with fat accumulating inside liver cells. As this overload persists, the cells become stressed and inflamed, releasing molecular distress signals that summon immune cells and activate fibrotic pathways. Over time, this microscopic tension reshapes the liver’s architecture – causing liver scarring as stiff, fibrotic strands of collagen replace healthy tissue. What starts as subtle metabolic stress can ultimately progress to cirrhosis, liver failure, or even cancer – often before symptoms are apparent.

MASH affects about 25% of people worldwide and up to 40% of adults in Singapore, making it one of the most prevalent chronic liver diseases globally. Current treatment options rely largely on sustainable lifestyle changes, such as exercise, dietary adjustments, and better sleep, or on drug therapy. However, the first FDA-approved medication for MASH with fibrosis, Rezdiffra (resmetirom), approved in 2024, benefits only around 30% of patients. In addition, although the drug primarily targets thyroid hormone receptors in the liver, it acts systemically, potentially leading to unintended side effects in other organs.

Advancing improved and safer therapies for MASH

In search of a more precise and effective solution, a research team led by Assistant Professor Wang Jiong-Wei from NUS Medicine has developed a liver-targeted therapy that addresses MASH at its root cause.

Published in Science Advances, their approach focuses on shutting down ceramide production, a fat molecule that drives disease progression when present in excess, using a lipid nanoparticle (LNP) platform to deliver Sptlc2-targeting siRNA specifically into liver cells.

To form the LNP-SPTLC2 siRNA, the team first screened seven proprietary siRNA sequences to obtain one that demonstrates the highest Sptlc2 gene silencing efficacy. The Sptlc2 gene plays a key role in the synthesis of ceramides. Next, lipids and the selected siRNA sequence are combined using a T-junction system, which provides a controlled mixing environment to reliably produce LNPs that are stable and homogenous in size.

The resulting LNP-SPTLC2 siRNA formulation was administered intravenously into laboratory models, and the ceramide level was monitored. The team observed that a single dose of LNP-SPTLC2 siRNA reduced Sptlc2 gene expression by 78%, which subsequently reduced the ceramide levels in both the liver and bloodstream.

Further investigation revealed that the reduction in ceramide levels decreased fat buildup in the liver through two ways: suppressing fatty acid uptake from external sources (e.g. bloodstream) and reducing fat synthesis within liver cells. Not only did this targeted intervention reduce fat accumulation but it also reduced inflammation and fibrosis, and slowed the overall progression of MASH in both short-term and long-term laboratory models.

Because ceramides also play essential roles in normal physiology, such as cell signalling, apoptosis, and skin barrier integrity, the researchers also assessed the therapy’s safety in other organs. Although some LNPs accumulated in the spleen, ceramide levels there remained unchanged, indicating that the treatment’s effects were confined to the liver.

The findings open the door for lipid-based nanomedicines as a new class of targeted treatments for fatty liver disease. By lowering harmful ceramide levels, this approach offers hope to millions of patients worldwide. Beyond liver disease, the team is also looking at adapting their methodology to treat other diseases, such as cardiovascular disease, where ceramides play a detrimental role.

Bringing innovation to clinical care

Recognising the urgency of translating this discovery into a viable treatment, Asst Prof Wang is actively working to advance the project towards medical intervention. By collaborating closely with various avenues of support, the team aims to build the necessary momentum to steer this innovation towards real-world application.