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Researchers in Singapore have developed a novel nanomedicine that successfully reduces liver fat, inflammation, and scarring in preclinical models of fatty liver disease. The therapy, which uses tiny, fat-like particles to deliver a gene-silencing drug directly to liver cells, offers a promising new strategy for a condition that affects one-quarter of the world’s population and has very few effective treatments. The new approach tackles a root cause of the disease by shutting down the production of harmful fats called ceramides, which are known to drive liver damage.
This development addresses a critical gap in treating metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease previously known as non-alcoholic fatty liver disease (NAFLD). Led by a team at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), the research demonstrates how a precision RNA-based therapy can be engineered to correct the specific cellular malfunctions that lead to the disease. By targeting a key enzyme responsible for ceramide synthesis, the lipid nanoparticle treatment effectively slowed disease progression in laboratory tests, paving the way for a potential new class of therapies for MASH and other related metabolic disorders. The findings were published in the peer-reviewed journal Science Advances.
A Widespread and Untreated Condition
Metabolic dysfunction-associated steatohepatitis is a growing global health epidemic, closely linked to rising rates of obesity and type 2 diabetes. The condition is estimated to affect approximately 25% of people worldwide and is even more prevalent in some regions, with up to 40% of adults in Singapore affected. The disease begins with the simple accumulation of excess fat in the liver, a stage known as steatosis. For a significant portion of individuals, this progresses to MASH, which is characterized by not only fat buildup but also dangerous inflammation and cellular damage.
Over time, this persistent inflammation leads to fibrosis, the formation of scar tissue within the liver. As scarring becomes more severe and widespread, it can advance to cirrhosis, a late-stage condition where the liver is permanently damaged and its function is severely impaired. Patients with cirrhosis face a high risk of life-threatening complications, including liver failure and liver cancer. Despite its prevalence and serious consequences, the therapeutic landscape for MASH has been remarkably challenging. For years, no approved medications were available, with lifestyle changes like diet and exercise being the primary recommendations. Recently, the U.S. Food and Drug Administration (FDA) has approved two drugs for the condition, but these treatments only benefit a minority of patients—approximately 30%—leaving a substantial unmet need for more effective and widely applicable therapies.
Identifying the Molecular Culprit
The research team at NUS Medicine focused on understanding the underlying molecular drivers of MASH to design a more targeted therapy. Their investigation centered on ceramides, a class of waxy lipid molecules that, while essential for normal cell function in small amounts, become toxic when they accumulate. High levels of ceramides in the liver are known to promote insulin resistance, inflammation, and cell death, all of which are hallmark features of MASH progression. The scientists hypothesized that halting the overproduction of these harmful fats could be a key to stopping the disease in its tracks.
Through analysis of both laboratory models and patient samples, the researchers confirmed that individuals with fatty liver disease had abnormally high concentrations of ceramides in their liver and blood. This overabundance was linked to the overactivation of an enzyme called serine palmitoyltransferase long chain base subunit 2, or SPTLC2. This enzyme is a critical component in the primary pathway that synthesizes ceramides in the body. By identifying the SPTLC2 gene as the central controller of this pathological process, the team pinpointed a clear and precise target for a potential therapeutic intervention. The goal became to specifically reduce the expression of the SPTLC2 gene within the liver, thereby cutting off the supply of excess ceramides at the source.
A Nanoparticle-Based Delivery System
Engineering the Vehicle
To deliver a drug that could act on a specific gene inside liver cells, the researchers turned to nanotechnology. They engineered a delivery system using lipid nanoparticles (LNPs), which are microscopic spheres made of fat-like materials. This technology has gained significant prominence in recent years, most notably as the delivery vehicle for the mRNA COVID-19 vaccines. The structure of LNPs allows them to encapsulate and protect fragile genetic drugs, such as RNA, as they travel through the bloodstream. Their lipid-based composition also helps them fuse with the membrane of target cells—in this case, liver cells—to release their therapeutic payload directly inside.
The Gene-Silencing Payload
The cargo carried by these specially designed nanoparticles was a small interfering RNA (siRNA), a type of genetic drug designed to silence a specific gene. The siRNA was engineered to recognize and bind to the messenger RNA (mRNA) produced by the SPTLC2 gene. In normal processes, mRNA carries the genetic instructions from DNA to the cell’s protein-making machinery. By binding to the SPTLC2 mRNA, the siRNA triggers a cellular mechanism that degrades the mRNA molecule before it can be used to produce the SPTLC2 enzyme. This process, known as RNA interference, effectively “switches off” the target gene without altering the cell’s underlying DNA. This highly specific action ensures that only the production of the ceramide-producing enzyme is halted, minimizing the risk of off-target effects on other vital cellular functions.
Significant Success in Preclinical Studies
The therapeutic strategy was tested extensively in laboratory models designed to mimic human MASH. The results were overwhelmingly positive. When the siRNA-loaded nanoparticles were administered, they successfully reduced ceramide levels in both the liver and the bloodstream. This biochemical change translated into significant clinical improvements. The models showed a marked reduction in fat accumulation in the liver, a decrease in inflammatory markers, and a substantial reduction in fibrosis, indicating that the scarring process was being halted or even reversed. The treatment effectively slowed the overall progression of the disease.
Importantly, the therapy proved effective in both short-term and long-term models of the disease, suggesting its potential for treating both early-stage and more advanced MASH. Furthermore, the researchers conducted rigorous safety evaluations and found no evidence of harmful effects in other organs, underscoring the targeted nature of the LNP delivery system. As Assistant Professor Wang Jiong-Wei, the study’s lead investigator, stated, “Our study shows that shutting down harmful liver fats with RNA nanomedicines can significantly reduce liver fat, inflammation, and scarring.” He emphasized that the work “identifies a clear molecular target in fatty liver disease and demonstrates how liver-targeted RNA medicines can directly address the root cause.”
Future Outlook and Broader Potential
This research marks a significant step forward in the quest for an effective MASH treatment. By validating the SPTLC2 gene as a viable therapeutic target and demonstrating the efficacy of a targeted RNA nanomedicine, the study provides a strong foundation for future clinical trials in humans. The approach offers a more precise and potentially safer alternative to systemic therapies that can have widespread effects throughout the body. The success of this strategy could herald the arrival of a completely new class of treatments for fatty liver disease, leveraging the power of RNA interference to correct disease-causing pathways at their genetic source.
The implications of this work may extend well beyond liver health. Since elevated ceramide levels have also been linked to a variety of other common metabolic conditions, including heart disease, obesity, and diabetes, this therapeutic approach could have a much broader impact. A treatment that safely lowers systemic ceramide levels might one day be used to help patients manage a range of related disorders. The team’s continued research will focus on refining the nanoparticle therapy and moving it toward the clinical trials necessary to confirm its safety and efficacy in patients, offering a new source of hope for millions affected by metabolic diseases worldwide.
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