Researchers uncovered how a high-cholesterol diet weakens the liver’s defenses and lowered LDL in mice by blocking the pathway, pointing to a potential new use for a shelved heart failure drug.
A diet high in cholesterol can gradually weaken the liver’s ability to remove harmful cholesterol from the blood. Cholesterol-related heart disease remains the leading cause of death worldwide, even as doctors have gained more medications to treat it.
Researchers at the University of California San Diego School of Medicine have identified a previously unknown biological pathway that helps explain why the liver’s cholesterol-clearing capacity declines. Their study, published in Nature, combined experiments in mice and human cells and identified a potential treatment target. An experimental drug that acts on that target has already undergone initial safety testing in humans, potentially shortening the route to a clinical trial for high cholesterol.
More receptors, more cholesterol cleared
The liver normally removes cholesterol from the blood so it can be broken down and used elsewhere. Proteins called LDL receptors sit on the surface of liver cells, where they capture harmful low-density lipoprotein (LDL) cholesterol and pull it inside for processing. More receptors mean more cholesterol can be cleared. Most cholesterol-lowering drugs, including statins and PCSK9 inhibitors, work by increasing or preserving the number of these receptors.
Some patients, however, cannot tolerate the side effects of available 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,” 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 pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap.”
Blocking CTSA lowers LDL in mice
The newly identified pathway works against cholesterol removal by gradually depleting LDL receptors. It begins when high dietary cholesterol activates Ral, a protein Saltiel previously studied in fat cells. As Ral activity increases, fewer LDL receptors remain available to pull cholesterol from the bloodstream, contributing to higher blood cholesterol.
That receptor loss ultimately depends on an enzyme called cathepsin A, or CTSA. When the researchers blocked CTSA with a small molecule inhibitor, they stabilized LDL receptors and sharply lowered circulating LDL cholesterol in mice.
“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 Saltiel. “This new discovery explains a critical piece of that puzzle.”
A shelved drug could target cholesterol
Turning a biological discovery into a treatment usually requires substantial additional research to find a suitable drug. In this case, a CTSA inhibitor had already been developed as a potential treatment for heart failure. It reached a Phase 1 clinical trial, where it was successfully tested for safety, before being shelved for strategic reasons.
That earlier work could allow the investigational drug to move into a Phase 2 trial for high cholesterol. The reduction in LDL cholesterol demonstrated in mice has yet to be established in people.
“Luckily, there’s an experimental drug sitting on the shelf that’s already been shown to be safe in humans,” said Saltiel. “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.”
Reference: “Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover” by Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Priyadarshini Jaishankar, Pusu Yang, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Linmeng Han, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva, Philip L.S.M. Gordts, Adam R. Renslo, Peng Zhao, Amit R. Majithia and Alan R. Saltiel, 24 June 2026, Nature.
DOI: 10.1038/s41586-026-10697-z
This study was funded, in part, by the National Institutes of Health (Grants P30DK063491, R01DK117551, R01DK128796, and R01DK135289) and an American Diabetes Association postdoctoral fellowship (1-25-PDF-76).
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.