Breakthrough treatment offers new hope in the fight against fatty liver disease

Metabolic liver disease might not get as much attention as heart disease or diabetes, but it affects around one in four people worldwide. Once called non-alcoholic fatty liver disease, this condition now goes by the name metabolic dysfunction-associated steatotic liver disease, or MASLD.

When it becomes more serious, it turns into MASH—short for metabolic dysfunction-associated steatohepatitis. These diseases begin with fat building up in liver cells, but can worsen to involve inflammation, cell damage, and eventually cirrhosis, a potentially fatal liver condition.

While these liver diseases are tied to diet, exercise, and body weight, what happens inside the cells tells a much deeper story. One part of that story involves a key molecule: NAD+, short for nicotinamide adenine dinucleotide.

This molecule helps keep cells alive, powers metabolism, and supports DNA repair. But in MASLD and MASH, NAD+ levels drop—and that drop seems to help the disease take hold and progress.

NAD+ is vital for many processes in your body. It accepts and donates electrons in reactions that create energy. Without it, your liver can't keep up with basic needs like energy production or repairing damaged DNA. This becomes a problem when the liver is under constant stress from unhealthy fats and inflammation, as in MASLD or MASH.

Your liver can make NAD+ in a few ways, but one of the most important is through a process called de novo synthesis, which starts from the amino acid tryptophan.

During this process, an enzyme called ACMSD (short for α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) controls a crucial decision point. It can either let the pathway go toward making NAD+, or it can divert it away.

ACMSD is found mainly in the kidney and liver, but it's especially active in liver cells, which use nine times more tryptophan for NAD+ production than kidney cells do. That makes it a key target if the goal is to boost NAD+ levels in the liver.

Researchers from EPFL, led by Johan Auwerx, wanted to know whether blocking ACMSD could help restore NAD+ in liver cells and reverse the damage seen in MASLD and MASH.

Previous research had already shown that inhibiting ACMSD could raise NAD+ levels in mouse liver. What was unknown was whether this boost would have a therapeutic effect in more complex models that mimic human liver disease.

To find out, Auwerx’s team used a powerful combination of mouse models, liver cell studies, and even human liver organoids, which are small, lab-grown mini-livers.

In one set of experiments, they fed mice a Western-style diet rich in fat to replicate the kind of liver stress seen in people with MASLD. Once signs of disease had appeared, they treated the mice with a new drug called TLC-065, designed to inhibit ACMSD.

The results were striking. Mice treated with TLC-065 showed higher NAD+ levels, less inflammation, and reduced DNA damage in their livers. There was also a significant drop in fibrosis, the scarring that often leads to cirrhosis.

When the researchers tested the same treatment on human liver organoids, they observed similar benefits, including reduced DNA damage signals.

One of the most surprising findings from the study was how closely DNA damage was tied to the development of liver disease. The researchers used transcriptome analysis to look at which genes were active in diseased liver cells. They found that DNA damage patterns were closely linked to the liver's disease status.

Further Mendelian randomization analysis, a statistical technique that uses genetics to test for cause-and-effect relationships, showed that DNA damage likely plays a direct role in raising ALT levels, a marker of liver injury.

This finding strengthens the case for a treatment that not only supports liver metabolism but also helps the liver repair its genetic material. By raising NAD+ levels through ACMSD inhibition, the liver becomes better equipped to fix DNA damage, which in turn may halt or reverse the disease process.

One challenge in liver research is translating what works in mice to what might work in people. That’s where the human liver organoid tests come in. These mini-livers mimic how real human livers behave in response to disease and treatment. The team’s success in reducing DNA damage and disease markers in these organoids strengthens the case that TLC-065, or other ACMSD inhibitors, could one day be used in human medicine.

With only one approved treatment currently available for MASLD and MASH, there’s an urgent need for better options. The study highlights ACMSD as a promising drug target. By blocking this enzyme, researchers can shift the body’s natural chemistry toward producing more NAD+, helping cells recover and protecting the liver from further harm.

The broader impact goes beyond one molecule or one disease. It underscores how metabolic health, DNA stability, and immune responses are all linked. NAD+ stands at the center of these connections, and restoring its balance may open doors not only for liver disease but for a wide range of metabolic disorders.

While more studies are needed before ACMSD inhibitors can be tested in humans, the early results are promising. For millions facing the risks of liver scarring, inflammation, and even liver failure, this new strategy offers hope. Instead of only treating symptoms, this approach targets the root chemical imbalances that drive the disease.

The study by Johan Auwerx and his team marks a major step in this direction. With NAD+ restored and DNA better protected, the liver has a fighting chance to heal—and so does the person who depends on it.

Research findings are available online in the journal of Hepatology.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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