Hidden Cholesterol Pathway Blocked by Drug Already Cleared for Safety Testing

What did the researchers find?

Working with mice and human cells, the team identified a previously unrecognized process that erodes this defense system. Over time, it reduces the number of LDL receptors, making it progressively harder for the body to keep blood cholesterol in check.

The chain of events starts with a protein called Ral, which Saltiel had previously studied in fat cells. The researchers found that eating large amounts of dietary cholesterol activates Ral, which triggers a cascade that ends with LDL receptors being destroyed. As Ral activity rises, fewer docking stations survive to remove harmful cholesterol from the blood.

The team then pinpointed a second critical player: an enzyme called cathepsin A, or CTSA, which helps drive the receptor-depleting process. When the scientists used a small-molecule inhibitor to block CTSA, the results were striking. LDL receptors became more stable, and circulating LDL cholesterol dropped sharply in the mice.

Crucially, this pathway is entirely separate from anything current cholesterol drugs target. That distinction matters for patients who don't respond adequately to existing medications.

"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 said. "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."

Why could this reach patients faster than usual?

Finding a new biological target normally starts a long drug development clock. Researchers typically need years to find a suitable compound and prove it's safe in people.

Here, that work may already be done. A CTSA-inhibiting drug had previously been developed as a potential heart-failure treatment. The program was later discontinued for strategic reasons, but the compound had already completed a Phase 1 clinical trial, where it was successfully evaluated for safety in humans.

Instead of starting from scratch, the researchers believe the existing inhibitor may be ready to move into a Phase 2 trial testing its effectiveness against high cholesterol.

"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."

What are the caveats?

The findings remain at an early stage. The dramatic LDL reductions were seen in mice, and the drug has not yet been shown to lower cholesterol in humans. The team's earlier Phase 1 data covers safety only, not effectiveness.

Still, the head start from prior clinical testing could meaningfully shorten the path to an answer in patients.

The study's co-authors span UC San Diego, UC San Francisco, the University of Texas Health Science Center at San Antonio and the University of Utah. The research received partial funding from the National Institutes of Health (grants P30DK063491, R01DK117551, R01DK128796 and R01DK135289) and an American Diabetes Association postdoctoral fellowship (1-25-PDF-76).