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A new drug prevents weight gain and fatty liver by controlling magnesium in cells. It made mice stay slim despite lifelong exposure to an unhealthy diet. Credit: Stock

Scientists have unveiled a small-molecule drug that blocks weight gain and liver damage in mice forced to live on sugary, high-fat food.

The compound works by limiting magnesium inside mitochondria—the cell’s power plants—so energy keeps burning instead of stalling. Treated mice quickly slim down and show no signs of fatty-liver disease, hinting at a future therapy against obesity, heart trouble, and cancer tied to poor diets.

Breakthrough Drug Fights Fat and Liver Disease

Researchers at UT Health San Antonio, working with colleagues from the University of Pennsylvania and Cornell, have created a small-molecule drug that keeps mice from gaining weight or developing liver damage even when they eat a lifetime of sugary, high-fat food.

“When we give this drug to the mice for a short time, they start losing weight. They all become slim,” said Madesh Muniswamy, PhD, professor of medicine in the health science center’s Joe R. and Teresa Lozano Long School of Medicine. The study appears in Cell Reports.

“A drug that can reduce the risk of cardiometabolic diseases such as heart attack and stroke, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will make a huge impact.”

Magnesium’s Hidden Role in Metabolism

The team began by asking how magnesium shapes metabolism—the way cells make and burn energy called ATP. Magnesium is the body’s fourth-most abundant charged mineral, vital for blood sugar control, blood pressure, and bone strength. Yet the scientists discovered that an excess of magnesium inside mitochondria, the cell’s “power plants,” actually slows energy production.

“It puts the brake on, it just slows down,” said co-lead author Travis R. Madaris, doctoral student in the Muniswamy laboratory at UT Health San Antonio.

When the researchers deleted MRS2, a gene that shuttles magnesium into mitochondria, the animals burned sugar and fat more efficiently. The mice stayed lean and healthy, with liver and fat tissue showing no trace of diet-induced fatty liver disease.

Man Stepping on Brake Pedal

Magnesium acts like a brake on energy production, researchers found. Credit: Shutterstock Drug CPACC Mimics Genetic Effect

The drug, which the researchers call CPACC, accomplishes the same thing. It restricts the amount of magnesium transfer into the power plants. In experiments, the result was again: skinny, healthy mice. UT Health San Antonio has filed a patent application on the drug.

The mice served as a model system of long-term dietary stress precipitated by the calorie-rich, sugary and fatty Western diet. The familiar results of this stress are obesity, type 2 diabetes and cardiovascular complications.

“Lowering the mitochondrial magnesium mitigated the adverse effects of prolonged dietary stress,” said co-lead author Manigandan Venkatesan, PhD, postdoctoral fellow in the Muniswamy lab.

Joseph A. Baur, PhD, of the University of Pennsylvania, and Justin J. Wilson, PhD, of Cornell, are among the collaborators. “We came up with the small molecule and Justin synthesized it,” Madaris said.

Major Health Impact Potential “These findings are the result of several years of work,” Muniswamy said. “A drug that can reduce the risk of cardiometabolic diseases such as heart attack and stroke, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will make a huge impact. We will continue its development.”

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