Scientists at the University of California, San Diego School of Medicine have uncovered a previously unknown biological route by which high‑cholesterol diets impair the liver’s ability to clear low‑density lipoprotein (LDL) cholesterol. The work, published in Nature, shows that blocking a key enzyme in this route dramatically reduced circulating LDL in mice, and that an experimental drug targeting the enzyme has already cleared a Phase 1 safety trial in humans.
How the liver removes bad cholesterol
The liver is central to cholesterol regulation because it extracts LDL particles from the bloodstream through surface proteins called LDL receptors. More receptors allow the liver to pull greater amounts of LDL into cells for processing, a principle that underlies the effectiveness of statins and PCSK9 inhibitors, which either increase receptor numbers or prevent their degradation.
A hidden pathway uncovered
Using mouse models and cultured human cells, the UC San Diego team discovered that a protein named Ral becomes activated when dietary cholesterol is abundant. Activated Ral triggers a cascade that culminates in the activation of the enzyme cathepsin A (CTSA). CTSA then promotes the turnover of LDL receptors, reducing their presence on liver cells and allowing LDL to accumulate in the blood.
When the researchers administered a small‑molecule inhibitor of CTSA to mice, LDL receptors remained stable and circulating LDL levels fell sharply. The findings suggest that the Ral‑CTSA axis operates independently of the mechanisms targeted by existing cholesterol medicines, opening a potential therapeutic avenue for patients who do not achieve safe LDL levels with current drugs.
Repurposing a previous drug
The CTSA inhibitor used in the mouse experiments was originally developed for heart‑failure treatment but was discontinued for strategic reasons before reaching market. Importantly, the compound had already completed a Phase 1 clinical trial that demonstrated safety in humans. Because the safety profile is established, researchers believe the drug could move directly into Phase 2 trials to test efficacy against high cholesterol, potentially accelerating its development timeline.
“There’s a real need for new cholesterol‑lowering options, especially for people who can’t reach safe levels with existing medications,” said senior author Alan Saltiel, PhD, professor of medicine at UC San Diego. “This pathway is completely separate from anything that current drugs target, giving us a new opportunity to fill that gap.” Saltiel added that having a safety‑tested compound “sitting on the shelf” could allow a clinical trial to begin much sooner than starting from scratch.
The study was a collaborative effort involving researchers from UC San Diego, UC San Francisco, the University of Texas Health Science Center at San Antonio, and the University of Utah. Funding came in part from the National Institutes of Health (grants P30DK063491, R01DK117551, R01DK128796, and R01DK135289) and an American Diabetes Association postdoctoral fellowship.
While the results are limited to animal models and cell work, the early data provide a compelling proof of concept that inhibiting CTSA can preserve LDL receptors and lower LDL cholesterol. If subsequent human trials confirm these effects, the approach could complement or extend the benefits of statins and PCSK9 inhibitors, offering a novel strategy to combat heart disease, the world’s leading cause of death.
Steve Lopez is a Senior Editorial Columnist and Health & Public Policy reporter for News Raise. Steve focuses on healthcare advancements, medical technologies, and public health policies.
