Investigational CTSA Inhibitor Offers New Pathway for Cholesterol Control, Study in Nature Reveals
Key Insights
Researchers at UC San Diego discovered a previously unknown biological pathway involving the Ral (search) protein and cathepsin A (CTSA) (search) that drives LDL receptor depletion in response to high dietary cholesterol.
Blocking CTSA with a small molecule inhibitor stabilized LDL receptors and dramatically lowered circulating LDL cholesterol (search) in mice, according to findings published in Nature.
The CTSA inhibitor has already completed a Phase 1 clinical trial for heart failure and was proven safe in humans, potentially accelerating its path to a Phase 2 trial for high cholesterol.
Cholesterol-related heart disease (search) remains the leading cause of death worldwide, and despite an expanding arsenal of treatments, many patients still cannot achieve safe cholesterol levels or tolerate the side effects of available medications. Now, researchers from University of California San Diego School of Medicine have uncovered a hidden biological pathway that explains why high-cholesterol diets steadily erode the liver's ability to clear harmful low-density lipoprotein (LDL) cholesterol from the blood — and they have identified a drug candidate, already proven safe in humans, that could potentially target it. The results were published in Nature.
"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."
The Ral (search)-CTSA Axis: A New Mechanism of LDL Receptor Depletion
The liver serves as the primary organ for removing cholesterol from the bloodstream through LDL receptors that sit on the surface of liver cells. These receptors function as docking stations, capturing LDL cholesterol (search) and pulling it inside the cell for processing. The more LDL receptors present on liver cells, the more cholesterol gets cleared — a principle that underpins most current cholesterol-lowering therapies, including statins (search) and PCSK9 inhibitors (search), which work by preserving or increasing the number of these receptors.
The new research, conducted in both mice and human cells, reveals a previously unknown mechanism that quietly counteracts this cholesterol removal process by gradually reducing LDL receptor numbers. The team discovered that this process is initiated when a protein called Ral (search) — which Saltiel has previously studied in fat cells — is activated by high dietary cholesterol. As Ral activation increases, fewer LDL receptors remain available to clear cholesterol from the blood.
This depletion process ultimately depends on an enzyme called cathepsin A (CTSA) (search). The researchers demonstrated that blocking CTSA with a small molecule inhibitor was sufficient to stabilize LDL receptors and dramatically lower circulating LDL cholesterol (search) in mice.
A Shelved Drug with Renewed Potential
Typically, translating a fundamental biological discovery into a therapeutic candidate requires years of additional research. However, in a notable turn of events, a CTSA inhibitor had already advanced through early-stage drug development with the initial goal of treating heart failure. Although it was eventually shelved for strategic reasons, the drug successfully completed a Phase 1 clinical trial where it was tested and proven safe in humans.
"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," said Saltiel. "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."
The existing safety data positions this investigational drug for accelerated evaluation. "Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans," Saltiel added. "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, titled "Dietary cholesterol activates an Ral (search)-dependent pathway driving LDLR turnover," represents a collaboration involving 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. The research was funded in part by the National Institutes of Health and an American Diabetes Association postdoctoral fellowship.