New Cholesterol Pathway and Drug Candidate

Researchers at University of California, San Diego School of Medicine, led by Alan R. Saltiel, have discovered a previously unknown biological pathway that explains how high-cholesterol diets reduce the liver's ability to clear harmful LDL cholesterol from the blood. They identified that a protein called Ral, activated by high dietary cholesterol, leads to the depletion of LDL receptors through an enzyme called cathepsin A (CTSA). Blocking CTSA with a small molecule inhibitor was shown to stabilize LDL receptors and dramatically lower cholesterol in mice. A CTSA inhibitor, previously developed for heart failure and proven safe in Phase 1 human trials, is now considered a promising candidate for a Phase 2 trial for high cholesterol, offering a new treatment option for patients who cannot achieve safe cholesterol levels with existing drugs like statins. The findings were published in Nature (journal) and supported by funding from the United States — National Institutes of Health and the American Diabetes Association.