Researchers at the University of California San Diego School of Medicine have uncovered a previously unknown biological pathway that explains how diets high in cholesterol gradually weaken the liver’s ability to clear harmful low-density lipoprotein (LDL) cholesterol from the bloodstream. The findings, published in Nature, identify both a hidden driver behind persistent high cholesterol and an experimental drug that has already passed initial human safety trials and could potentially target it.
Heart disease linked to high cholesterol continues to be the leading cause of death worldwide. Although physicians currently rely on medications such as statins and PCSK9 inhibitors, many patients still struggle to reach safe lipid levels or experience side effects that make existing therapies difficult to maintain. The new discovery targets a mechanism entirely separate from standard treatments, offering a potential path forward for patients who do not respond adequately to current drugs.
“We’ve known for a long time that a high-cholesterol diet reduces the liver’s ability to clear cholesterol from the blood, but we didn’t fully understand why,” said senior author Alan Saltiel, PhD, professor of medicine at UC San Diego School of Medicine and director of the UC San Diego/UCLA Diabetes Research Center. “This new discovery explains a critical piece of that puzzle.”
How Liver Receptors Clear Blood Cholesterol
The liver plays a central role in managing lipid levels by extracting cholesterol from circulation so it can be broken down and processed by the body. Liver cells accomplish this using surface structures known as LDL receptors, which act as docking stations to capture circulating LDL particles and draw them inside.
When liver cells maintain a higher density of these receptors, they can clear more cholesterol from the bloodstream. Standard cholesterol-lowering drugs work primarily by preserving or increasing this receptor supply. However, long-term consumption of high-cholesterol diets triggers a counterproductive chain reaction that diminishes receptor numbers over time, making it increasingly difficult for the body to regulate blood lipids.
Through experiments involving mice and human cells, the research team traced this receptor loss to a protein called Ral, which Saltiel had previously investigated in fat cells. High dietary cholesterol activates Ral, initiating a series of cellular events driven by an enzyme called cathepsin A (CTSA). As CTSA activity promotes the depletion of LDL receptors, clearance rates plummet.
When scientists used a small molecule inhibitor to block CTSA in laboratory experiments, the results were striking. LDL receptors stabilized, and circulating LDL cholesterol levels dropped dramatically in mice. Because this pathway operates independently of standard drug targets, researchers believe it could provide an alternative treatment avenue.
“There’s still a real need for new cholesterol-lowering options, since some people can’t get to safe levels even with the drugs we have now,” Saltiel noted. “This new pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap.”
Repurposing a Shelved Heart Failure Drug
Translating biological targets into approved therapies typically requires years of early-stage compound development and preclinical testing. In this instance, however, researchers have identified a viable candidate already advanced through initial human evaluation. An experimental inhibitor designed to block CTSA had previously been developed as a potential treatment for heart failure. Although that program was eventually discontinued for strategic reasons, the medication successfully cleared a Phase 1 clinical trial, establishing a safety baseline in humans.
This prior development history could allow investigators to proceed toward a Phase 2 clinical trial to investigate its effectiveness against high cholesterol. While the experimental compound has not yet been proven to lower cholesterol in humans, its existing safety data provide a significant head start.
“Luckily, there’s an experimental drug sitting on the shelf that’s already been shown to be safe in humans,” Saltiel said. “We hope to test whether this might be effective by conducting a clinical trial — which could potentially bring a new treatment option to patients much sooner than would have been expected.”
The study was co-authored by researchers from UC San Diego, the University of California, San Francisco, the University of Texas Health Science Center at San Antonio, and the University of Utah. Funding was provided in part by the National Institutes of Health and an American Diabetes Association postdoctoral fellowship.
Further progress depends on advancing the existing CTSA inhibitor into Phase 2 clinical trials to determine its effectiveness against high cholesterol.
