Scientists found a hidden driver of high cholesterol, and a drug against it passed an early safety trial

A protein called Ral turns out to act as a hidden switch between a high-cholesterol diet and high blood cholesterol, according to University of California San Diego researchers. When dietary cholesterol activates Ral, liver cells lose LDL receptors, the molecular hooks that pull LDL cholesterol out of the blood. An experimental drug that blocks the process has already passed an early safety trial in people, though it has never been tested for lowering cholesterol.

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The work, published in Nature on June 24, 2026, rests on mice and human cells. Everything about the drug’s potential as a cholesterol treatment remains a hypothesis awaiting a trial.

Ral and the loss of LDL receptors on liver cells

LDL receptors sit on the surface of liver cells and clear LDL cholesterol from circulation, so the number of receptors largely sets how much LDL stays in the blood. The paper, titled “Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover,” reports that a cholesterol-rich diet switches on Ral, a protein senior author Alan Saltiel had previously studied in fat cells. The more Ral is activated, the fewer receptors remain. According to the Genetic Engineering and Biotechnology News account, Ral works through a complex of two proteins, RalBP1 and REPS1, to steer receptors toward destruction.

That destruction depends on cathepsin A, abbreviated CTSA, an enzyme inside the cell’s lysosome that degrades the receptors. The pathway is distinct from those targeted by statins and by PCSK9 inhibitors, the two best-known classes of LDL-lowering drugs. Saltiel said the finding explains a critical piece of the puzzle of why dietary cholesterol raises blood cholesterol in the first place.

Co-authors include Amit R. Majithia of UC San Diego, with collaborators at the University of California San Francisco, the University of Texas Health Science Center at San Antonio and the University of Utah. The multi-site list matters because the claim spans diet, cell biology and pharmacology, three fields that rarely share one paper, and each link in the chain from cholesterol intake to receptor loss had to be shown separately.

A CTSA inhibitor that sharply lowered LDL in mice

If CTSA does the cutting, blocking it should preserve receptors. The team tested a selective small-molecule CTSA inhibitor in mice and found that it stabilized the LDL receptors and caused circulating LDL cholesterol to drop dramatically. The UC San Diego news story describes the result in those terms, without publishing percentages, group sizes or statistics, so the size of the effect has to be checked in the Nature paper itself.

Mice also handle cholesterol differently from people, which is why animal LDL drops have a long record of failing to translate. Human liver cells were part of the study, but the cell experiments do not reproduce the whole-body picture of diet, liver and blood, and no animal result in the sources says how long the LDL reduction lasted or whether it held up across different diets.

SAR164653, a shelved heart-failure drug

The inhibitor is not a new molecule. According to Genetic Engineering and Biotechnology News, the compound is SAR164653, which was developed for heart failure and advanced to a Phase 1 trial, where it was tested for safety. The program was later shelved for strategic reasons, and the UC San Diego account says the reason was not a safety concern. Saltiel said there is an experimental drug sitting on the shelf that has already been shown to be safe in humans.

A Phase 1 study answers a narrow question: whether a drug is tolerated in a small group of people at the doses tested. The sources do not report enrollment size or results, and nothing shows the drug lowers cholesterol in humans. Saltiel said the team hopes to run a clinical trial to test whether it works, but no such trial has been announced. A Phase 2 study in people with high cholesterol would be the next step.

Why a third pathway matters beyond statins

The Centers for Disease Control and Prevention describes LDL as the cholesterol that can build up as plaque in the arteries and lead to heart disease or stroke, and notes that millions of Americans have high cholesterol. Statins and PCSK9 inhibitors both work, yet some patients cannot tolerate statins or still miss their targets, and each existing class is aimed at a different step in how receptors are made or recycled.

A CTSA inhibitor would attack receptor loss, a step none of those drugs touch. Whether it adds to existing treatments or replaces them is unanswered. The study, funded in part by National Institutes of Health grants and an American Diabetes Association fellowship, also contributes an explanation that diet alone had lacked: ScienceDaily’s summary frames it as a hidden mechanism by which high-cholesterol diets disrupt the body’s natural cholesterol defenses. The test of whether that mechanism is also a drug target now depends on a Phase 2 trial that has yet to be launched.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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