For a disease that impacts so many, there are surprisingly few treatments available, but that may soon change
(Adobe photo)
Fatty liver disease is a slow, silent, and extremely common condition where symptoms may go unnoticed before it is too late.
Globally, billions of people live with this disease, and unfortunately, beyond lifestyle interventions, there are currently very few treatment options available. A team of researchers, including UConn School of Pharmacy and Pharmaceutical Sciences professor Xiaobo Zhong, Ph.D. candidates Jing Jin and Beshoy Armanios, have developed a new therapeutic strategy (U.S. Provisional Application No. 63/995,368) that could stop the disease and possibly reverse the damage already caused in many patients.
A Prevalent Disease
Within the liver, cells called hepatocytes perform a myriad of vital functions, and they comprise about 80% of the mass of the liver, says Zhong. These cells take up fatty acids from our diet, and they can also produce fatty acids from glucose. Hepatocytes also break down, store, and secrete fatty acids, and produce ketones from fatty acids when carbohydrates are not available. The amazing array of functions is crucial for metabolic and nutrient storage capacity in our bodies, but this also means that if there are disruptions in these carefully choreographed pathways, things can go very wrong.
"All of those pathways determine how much fatty acids accumulate in the cells. The disease can result if any of those pathways have something wrong, and it changes how they handle fatty acids. All can contribute," says Zhong.
When things go wrong, fatty liver diseases can progress through four major stages. The first stage, called Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), results when fat begins to accumulate in the liver.
"Nearly every family has somebody who has this. Most people with MASLD are fine for their whole life and they may not need treatment," says Zhong.
However, if the disease progresses, the next stage is called Metabolic Dysfunction-Associated Steatohepatitis (MASH), which usually has an onset of about 10-20 years after MASLD diagnosis.
"Around 400 million people globally develop MASH, that is fatty liver plus inflammation, so they have inflammatory markers in the blood," says Zhong. "About 50% of those MASH people will go on to develop fibrosis, and about 50% of those liver fibrosis patients will progress to cirrhosis where the liver can no longer perform metabolic functions."
Limited Treatment Options
The first line of management options for MASLD and MASH patients includes diet and exercise, but Zhong says this is still not sufficient for a lot of patients, because the liver can still make fatty acids from glucose. For this, patients can take medications that help control glucose levels. A newer drug approved by the FDA in 2024 for the treatment of MASH uses a different strategy by activating the thyroid receptor to help burn liver fat and reduce inflammation, but only a small portion of patients may benefit from this option, says Zhong.
If these measures do not help and the disease progresses to fibrosis, then to cirrhosis, the remaining treatment option available is liver transplant from a matched donor.
The array of pathways where things can go wrong and other aspects of fatty liver diseases have resulted in many challenges and failures in the development of therapeutic interventions, and Zhong says pharmaceutical companies are hesitant to put money into the development of new drugs. However, Zhong and his colleagues have developed a new method they are confident will spark new interest in finding a way to treat this disease.
A Promising New Approach
Zhong says that while current drug therapies for fatty liver diseases target downstream metabolic pathways, like controlling glucose levels, he and his team focused on a global regulator of hepatocyte functioning, a long noncoding RNA (lncRNA) called hepatocyte nuclear factor four alpha anti-sense RNA1 (HNF4A-AS1). Through a series of publications, they found HNF4A-AS1 is involved in the down-regulation of many liver functions, including lipid metabolism and drug metabolism, showing the importance of this lncRNA for liver functioning.
HNF4A-AS1 degrades the master regulator protein HNF4A, which controls transcription of over 1,000 genes that are important for metabolic functioning. With low levels of HNF4A, signs of liver disease begin to develop, where the liver begins to accumulate lipids, inflammation increases, insulin resistance develops, and drug metabolism functions are impaired, says Zhong.
"HNF4A seems to be an upstream master regulatory factor that controls all six pathways in fat accumulation in hepatocytes. The studies show that in most liver disease patients, this protein is down regulated."
Reversing down regulation is tricky, says Zhong,
"Normally if something is produced too much, it is easier to find something to interact with it to decrease it. However, this protein is already decreased, so we have to figure out what the activator is. It is very difficult to do this kind of activation."
For this, the researchers focused on antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) to target HNF4A-AS1 so that it cannot degrade HNF4A. With functional HNF4A, the liver is expected to function normally.
"We think we can reverse MASH and MASLD with this approach and we think this can help open a door for pharmaceutical companies to rethink their strategy to develop a drug," says Zhong. "The drug we propose to develop uses new classes of nucleic acid therapeutics called ASOs and siRNAs that are highly complementary to HNF4A-AS1 RNA sequence and once they match, the ASOs and siRNAs degrade the expression of that RNA. We hope this rebuilds HNF4A and the metabolic pathways," says Zhong.
Oligonucleotide-based drugs have an advantage over previous small molecule drug classes in that they have a longer therapeutic duration. Zhong notes a similar siRNA drug inclisiran for lowering cholesterol only needs to be administered twice per year, and this one would likely follow similar dosing schedule.
Zhong and his team are partnering with UConn's Technology Commercialization Services (TCS) to translate this promising research from the laboratory into meaningful societal impact. TCS is working closely with Zhong and his research team to identify an industry partner to advance and mature the technology. Strategic industry collaboration will provide critical development guidance, accelerate translational milestones, and help position the innovation for successful clinical and commercial advancement.
The researchers are confident this novel treatment approach will shed new light on drug discovery efforts. TCS is working with the team on patent protection and then commercialization, with hopes of garnering interest from a pharmaceutical company to partner with to develop the drug. If there is interest from pharmaceutical companies, the researchers plan to use the organ-on-a-chip platform to test candidate sequences. Once they determine top candidates, clinical studies can take place, and altogether, a drug could be available and on the market in several years.
"If you consider the population that could benefit from this type of drug, this is extremely exciting," says Zhong.
"Given the challenges and limitations of current therapeutic options, this new approach to treating fatty liver disease addresses a significant unmet need in the market," said TCS senior director of licensing Amit Kumar.
(This research is funded by a NIH grant of R35GM140862. U.S. Provisional Application No. 63/995,368 titled "HNF4A-AS1 targeting therapeutics and uses thereof" was filed on March 3, 2026.)
