New Drug Stops Weight Gain and Lowers Cholesterol by Targeting Nitric Oxide

Scientists have discovered an enzyme that drives fat production and shown that blocking it prevents weight gain and lowers cholesterol in mice.

Obesity is now one of the most widespread health challenges worldwide and is a major driver of preventable disease and early death. The condition significantly increases the risk of related illnesses, including heart disease and fatty liver disease (MASLD). These trends have accelerated as modern lifestyles increasingly favor high-calorie foods and reduced physical activity.

At the center of the new research is nitric oxide, a small gas molecule that acts as a powerful regulator of many biological processes.

Nitric oxide influences how cells function by binding to specific proteins and modifying their activity. When this signaling system becomes unbalanced, with either too much or too little nitric oxide attached to key proteins, normal metabolic control can break down and contribute to disease.

In findings published in the journal Science Signaling, scientists from University Hospitals and Case Western Reserve University uncovered a previously unknown enzyme known as SCoR2. The enzyme removes nitric oxide from proteins that govern how fat is stored and produced in the body. By eliminating nitric oxide from these proteins, SCoR2 switches on fat synthesis, demonstrating that the enzyme plays a central role in the body’s ability to generate fat and opening the door to new therapeutic strategies.

Turning off fat production

The researchers then blocked SCoR2 using both genetic methods and a newly developed drug. In mouse models, inhibiting this nitric oxide-removing enzyme prevented weight gain and reduced liver damage. The same drug also lowered levels of harmful cholesterol.

“We have a new class of drug that prevents weight gain and lowers cholesterol—a potential therapy for obesity and cardiovascular disease, with additional hepatic benefits,” explained lead author of the study, Jonathan Stamler, MD, President and Co-Founder, Harrington Discovery Institute, Distinguished University Professor, Robert S. and Sylvia K. Reitman Family Foundation Professor of Cardiovascular Innovation, and Professor of Medicine and of Biochemistry at University Hospitals and Case Western Reserve University.

“In the liver, nitric oxide inhibits the proteins that make fat and cholesterol. In fat tissue, nitric oxide inhibits the genetic program that makes the enzymes that create fat,” Dr. Stamler added.

A new path toward obesity treatment

Next steps in this research involve advancing the drug into clinical trials, which should take about 18 months.

“Our team looks forward to further developing a first-in-class drug to block weight gain and lower cholesterol, with favorable effects on liver health,” Dr. Stamler said.

Reference: “The protein denitrosylase SCoR2 regulates lipogenesis and fat storage” by Nicholas M. Venetos, Colin T. Stomberski, Hua-Lin Zhou, Zhaoxia Qian, Precious J. McLaughlin, Puneet K. Bansal, John Feczko, Ilya Bederman, Hoa Nguyen, Alfred Hausladen, Joseph C. Schindler, Zachary W. Grimmett, Henri Brunengraber, Richard T. Premont and Jonathan S. Stamler, 23 December 2025, Science Signaling.
DOI: 10.1126/scisignal.adv0660

Disclosure: The drug will be developed with the help of Harrington Discovery Institute at UH, which has a singular mission: To accelerate promising discoveries into medicines for unmet needs. Now in its 13^th year, Harrington Discovery Institute’s growing portfolio includes 227 medicines in the making; 75 institutions supported; 46 companies launched; 24 medicines in clinic; and 15 licenses to pharma.

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