The first approved drug for MASH, and why nuclear receptors matter

On March 14, 2024, the FDA approved resmetirom (Rezdiffra) for adults with MASH, the inflammatory form of fatty liver disease, with moderate to advanced liver scarring. It is the first approved drug for the condition.

MASH stands for metabolic dysfunction-associated steatohepatitis. Until recently it was called NASH. It begins with fat building up in liver cells, often alongside obesity and type 2 diabetes. In some people, that fat triggers inflammation and damage, and over time scar tissue builds up. Advanced scarring can lead to cirrhosis, liver failure and liver cancer.

Until now, the main advice for patients has been weight loss and lifestyle change. Those work, but they are hard to achieve and maintain, and for people who already have significant scarring there was no approved drug. That is why this approval matters.

How it works

Resmetirom activates a thyroid hormone receptor in the liver, a nuclear receptor that helps control how the liver burns fat.

Thyroid hormone has long been known to increase fat burning and lower cholesterol, but giving it broadly causes side effects in the heart and bones. Resmetirom was designed to act mainly on the form of the receptor found in the liver. The goal is to get the metabolic benefit where it is needed while avoiding the effects elsewhere.

A strong validation of years of basic research.

Nuclear receptors are proteins that sit inside the cell, bind to hormones or nutrients, and then switch sets of genes on or off. They are a direct link between what the body senses and how cells respond. In the liver, they help decide whether fat is stored or burned.

My perspective

This is the class of proteins I worked on in our FBXW7 study: nuclear receptors that sense nutrients and decide how the liver handles fat. Seeing a drug that acts on that logic reach patients is a strong validation of years of basic research.

Basic research often looks far from patients. Studying how a protein is regulated, or which genes a receptor controls, does not sound like drug development. But approvals like this one depend on that kind of work. Someone had to understand the receptor, its forms and what it does in the liver before anyone could design a drug that targets it selectively.

I would also add some caution. Approval is based on improvements in liver tissue, and longer follow-up is still needed to confirm benefits on outcomes like cirrhosis and survival. Not every patient will respond, and the drug addresses one part of a disease that is closely tied to diet, weight and metabolism. It is a tool, not a replacement for treating those underlying factors.

It will not be the last. Fatty liver disease affects a large share of adults, and there are other switches in the same network worth targeting. Other nuclear receptors and metabolic regulators are being studied for the same disease, and combinations may eventually work better than any single drug.

For me, the main lesson is that understanding how cells sense nutrients is not an abstract question. It leads to treatments.