MASH is the severe, progressive form of fatty liver disease, marked not merely by fat accumulation in the liver but by persistent inflammation and tissue scarring, known as fibrosis. Left unchecked, it can advance to cirrhosis, liver failure and liver cell cancer. The condition has become increasingly common, particularly in Singapore and other westernised Asian populations, where estimates suggest prevalence may reach up to 40 per cent. While obesity remains the dominant risk factor, a growing proportion of people worldwide, especially across Asian populations, have developed MASH despite maintaining a normal body mass index. This clinical entity has come to be known as lean MASH, and its environmental triggers and molecular underpinnings have remained stubbornly unclear, in part because no suitable laboratory models existed to study it.

That gap is precisely what the Duke-NUS-led team, which included researchers from National Heart Centre Singapore, Duke University School of Medicine and University College London, set out to close. Their newly developed mouse model mirrors the key features of lean MASH observed in patients: relatively low levels of fat in the liver, but severe inflammation and scarring. This pattern matters clinically, because some patients with less liver fat nonetheless face a higher risk of serious liver complications and death. By reproducing this phenotype in the laboratory for the first time, the researchers have created an experimental platform that allows the disease to be dissected at the molecular level, something previously impossible when the only available models reflected the obesity-associated form of the condition.

At the heart of the study is a deceptively simple dietary factor: salt. The researchers found that excess dietary salt changes how the liver handles fat, increasing fat breakdown while simultaneously activating immune cells that drive inflammation within the liver. In other words, the high-salt diet caused MASH in both lean and obese mice, but through different mechanisms. In the lean model, the damage appears to arise not from an overload of fat but from a metabolic and inflammatory shift triggered by salt itself. The published article describes the lean MASH phenotype as involving increased hepatic urea cycle activity and a process called EIF5A hypusination, pointing to specific biochemical alterations that accompany the salt-driven disease state.

The implications of this distinction are significant for drug development and patient care. Most current therapeutic strategies for MASH have been designed around the biology of obesity-associated disease, in which excess fat accumulation is the central driver. If lean MASH is propelled instead by salt-induced metabolic and inflammatory changes, treatments that succeed in obese patients may fall short in lean ones. Dr Zhou Jin, lead author of the study and Principal Research Scientist at Duke-NUS’ Cardiovascular & Metabolic Disorders Signature Research Programme and Gilead Research Scholar, emphasised this point. “Our findings suggest that lean MASH is not simply the same disease occurring in a thinner person. The biology appears to be different,” she said. “While obesity-associated MASH is closely linked to excess fat accumulation, our model shows that high dietary salt can alter liver metabolism and activate inflammatory pathways even without obesity. That distinction matters because treatments developed for obesity-associated MASH may not address what is driving disease in lean patients.”

The study also broadens the clinical horizon beyond the liver itself. Cardiovascular disease is a primary cause of mortality among patients with MASH, which means that a relevant experimental model of the lean form of the disease could have consequences for heart research as well. Professor Derek John Hausenloy of the Cardiovascular & Metabolic Disorders Signature Research Programme at Duke-NUS and one of the study’s authors highlighted this whole-body perspective. “This model gives us a way to investigate and understand lean MASH as a whole-body disease, not just a liver condition,” he said. “That is particularly important because cardiovascular disease is a leading cause of death in patients with MASH. We can now begin to ask whether the mechanisms driving liver injury in lean MASH also affect the heart.”

Institutional leaders at Duke-NUS framed the work as a challenge to long-standing assumptions in hepatology. Professor Lok Shee-Mei, Vice-Dean of the Office of Research at Duke-NUS, noted that the study undermines the idea that fatty liver disease follows a single biological pathway in every patient. “By revealing a distinct mechanism in lean MASH, and providing a preclinical model with which to study it, the team has created an important foundation for developing diagnostics and treatments that reflect the biology of the individual patients,” she said. Her comments underscore a broader shift in metabolic medicine towards precision approaches, in which the same diagnosis may require different interventions depending on the underlying molecular drivers in each patient.

The research, published under the title describing high salt supplementation of a MASH-inducing diet causing a lean MASH phenotype with increased hepatic urea cycle activity and EIF5A hypusination, appeared in the 1 September 2026 issue of Molecular Metabolism. The method of research was an experimental study using animal tissue samples, and the work was supported by the Singapore Ministry of Health through the National Medical Research Council, including the NMRC Clinician Scientist Award in the Senior Investigator Category and the National Research Foundation Singapore under the NMRC Open Fund Individual Research Grant. This funding infrastructure reflects Singapore’s strategic investment in metabolic disease research, an area of acute relevance to Asian populations where lean MASH appears disproportionately common.

Looking ahead, the team plans to use the new model to identify early diagnostic biomarkers of lean MASH and to test compounds capable of selectively blocking the salt-induced inflammatory pathways identified in the study. Such biomarkers could allow clinicians to distinguish lean MASH earlier in its course, when intervention is most effective, and to determine which treatments are most likely to benefit individual patients. If salt-driven inflammation proves to be a tractable drug target, the findings could eventually reshape dietary guidance as well, adding liver protection to the long list of health reasons to moderate sodium intake. For now, the study stands as a striking demonstration that a common dietary component may be reshaping liver biology in ways that obesity alone cannot explain.

For the millions of people worldwide who carry normal weight but abnormal liver chemistry, the research offers both an explanation and a direction. It suggests that lean MASH deserves recognition as a distinct disease entity with its own mechanisms, its own models and, ultimately, its own tailored therapies. As the Duke-NUS team and its collaborators in Singapore, the United States and the United Kingdom continue to probe the salt-inflammation axis in the liver, the study may mark the beginning of a more nuanced era in the understanding and treatment of fatty liver disease, one in which a patient’s body weight is no longer assumed to define the biology of their illness.

Subject of Research: Salt-induced mechanisms of lean metabolic dysfunction-associated steatohepatitis studied in a novel mouse model

Article Title: High-salt diet may drive fatty liver disease differently in lean people: Duke-NUS pre-clinical study

Article References: High-salt diet may drive fatty liver disease differently in lean people: Duke-NUS pre-clinical study. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: fatty liver disease, MASH, lean MASH, high-salt diet, Duke-NUS, liver inflammation, liver fibrosis, mouse model, Molecular Metabolism, hepatic metabolism, cardiovascular disease, precision medicine