Researchers at MIT have developed advanced tissue models that replicate how the human liver works, potentially accelerating the discovery of new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), a condition affecting over 100 million people in the United States. These "liver-on-a-chip" models incorporate blood vessels and immune cells, allowing scientists to study how liver disease develops in ways that traditional animal testing cannot. \n\nWhy Current Drug Testing Falls Short for Liver Disease \n\nThe challenge with developing new liver disease treatments is that mice and other animal models don't accurately replicate human liver biology. Pharmaceutical companies have used simpler tissue models for decades to test whether drugs damage the liver, but these basic systems can't effectively model the disease states that actually matter to patients. \"There are already tissue models that can make good preclinical predictions of liver toxicity for certain drugs, but we really need to better model disease states, because now we want to identify drug targets, we want to validate targets,\" explains Linda Griffith, a professor of biological engineering and mechanical engineering at MIT and senior author of the research. \n\nThis gap in testing capability has real consequences. Currently, only two medications are FDA-approved to treat metabolic dysfunction-associated steatohepatitis (MASH), the more severe form of fatty liver disease that involves inflammation and scarring. One of these drugs, resmetirom, only works effectively in about 30 percent of patients—a limitation that researchers are now investigating using these new tissue models. \n\nHow the New Liver Models Work \n\nThe MIT team created two advanced tissue models published in recent research. The breakthrough involves growing tiny clusters of liver cells within a network of functional blood vessels that can carry fluid through the tissue. This architecture allows immune cells to flow through the tissue just as they would in a real liver, creating a much more realistic environment for studying disease. \n\nThe researchers built these models using a modified version of the \"LiverChip,\" a microfluidic device originally developed in the 1990s. To create a model of MASLD, they exposed the tissue to high levels of insulin, glucose, and fatty acids—the same metabolic conditions that occur in patients with the disease. This exposure caused fat to accumulate in the tissue and triggered insulin resistance, a hallmark of MASLD that often leads to type 2 diabetes. \n\nWhat the Models Revealed About Current Treatments \n\nWhen researchers treated their MASLD tissue models with resmetirom, they discovered something unexpected: the drug triggered an increase in immune signaling and inflammation markers. This finding may help explain why the drug doesn't work for all patients. \"Because resmetirom is primarily intended to reduce hepatic fibrosis in MASH, we found the result quite paradoxical,\" said Dominick Hellen, lead author of the resmetirom study. \"We suspect this finding may help clinicians and scientists alike understand why only a subset of patients respond positively to the thyromimetic drug\". \n\nThe discovery highlights a critical advantage of these tissue models: they can reveal unexpected drug effects that might not show up in simpler testing systems or animal studies. This information could help doctors better predict which patients will benefit from resmetirom and guide the development of new treatments that work through different mechanisms. \n\nHow These Models Could Accelerate Drug Development \n\n \n- Disease State Testing: Unlike traditional models that only test drug toxicity, these systems can replicate actual disease conditions like MASLD and MASH, allowing researchers to identify which drug targets work best at different disease stages. \n- Patient Response Prediction: By studying how different liver tissues respond to drugs, researchers can better understand why some patients benefit from treatments while others don't, potentially leading to personalized medicine approaches. \n- Reduced Animal Testing: More accurate human tissue models mean fewer drugs need to be tested in animals before moving to human trials, accelerating the overall development timeline. \n- Cost Efficiency: Tissue models are less expensive and faster to work with than animal studies, allowing pharmaceutical companies to test more drug candidates and combinations. \n \n\nWhat's Next for Liver Disease Treatment? \n\nGriffith emphasizes that finding new drugs remains a priority because relying on a single medication or drug class is risky. \"You're never declaring victory with liver disease with one drug or one class of drugs, because over the long term there may be patients who can't use them, or they may not be effective for all patients,\" she explains. The new tissue models provide a powerful tool for identifying and validating new drug targets, potentially leading to treatments that work for patients who don't respond to current options. \n\nThe research represents the latest advancement in a broader effort to use microphysiological systems—sophisticated tissue models that mimic organ function—to explore human liver biology. As these models become more sophisticated and widely adopted by pharmaceutical companies, they could significantly accelerate the pace of drug discovery for the millions of Americans living with fatty liver disease and its more serious complications. "\n}
