Alan Saltiel was sipping coffee in his San Diego lab one morning when the data finally clicked—mice fed a high-cholesterol diet weren’t just accumulating fat in their livers; they were silently disarming their own defenses. For years, scientists knew that too much dietary cholesterol weakened the liver’s ability to clear LDL from the blood, but the precise mechanism remained a mystery. Now, Saltiel and his team at UC San Diego School of Medicine have uncovered a hidden biological pathway that explains how cholesterol sabotages its own removal—and they’ve found a potential way to stop it.
High cholesterol remains the world’s leading contributor to heart disease, responsible for millions of deaths annually. While statins and PCSK9 inhibitors have helped many patients, a significant number still struggle to reach safe LDL levels or can’t tolerate side effects. The liver, the body’s primary cholesterol processor, relies on LDL receptors to pull LDL out of circulation. More receptors mean cleaner blood—but high cholesterol does something insidious: it steadily reduces their number. Saltiel’s team discovered that this begins with a protein called Ral, previously studied in fat metabolism, which gets activated by excess dietary cholesterol. Once switched on, Ral triggers a chain reaction that leads to the degradation of LDL receptors.
The final culprit? An enzyme called cathepsin A (CTSA). In experiments with both mouse models and human liver cells, the researchers found that CTSA acts as the executioner, breaking down LDL receptors once Ral sets the process in motion. But when they blocked CTSA with a small-molecule inhibitor, something remarkable happened: LDL receptors stabilized, and circulating LDL cholesterol dropped dramatically in mice. This wasn’t just a minor adjustment—it was a systemic reset of the liver’s cholesterol-clearing capacity.
Even more promising, the inhibitor isn’t starting from scratch. Originally developed for heart failure, a CTSA-blocking drug had already passed a Phase I clinical trial, proving safe in humans before being shelved for strategic reasons. "We don’t have to wait years to develop a new drug," Saltiel said. "It’s already been tested. We just need to test whether it works for cholesterol."
This discovery opens a door to a completely new class of cholesterol-lowering therapies—one that operates independently of statins or PCSK9 inhibitors. With heart disease still the top cause of death globally, a new mechanism could be transformative, especially for patients who don’t respond to current treatments. The next step is a Phase II trial to test the repurposed drug in people with high cholesterol. If successful, a therapy that once seemed abandoned could soon offer a second chance—for both the drug and the patients who need it most.