Heart disease fueled by high cholesterol continues to remain the leading cause of death worldwide, posing a persistent challenge to global public health systems and medical practitioners alike. Despite the introduction of an unprecedented array of advanced treatment options over recent decades, a significant portion of patients still struggle to lower their low-density lipoprotein (LDL) cholesterol to safe, manageable levels. Furthermore, a considerable number of individuals experience adverse side effects from existing pharmaceutical interventions, making standard medications difficult to tolerate or take consistently over the long term.
Addressing this critical medical need, a team of researchers at the University of California San Diego School of Medicine has now identified a previously unknown biological pathway that helps explain a fundamental physiological mystery: why diets high in cholesterol gradually weaken the body’s natural ability to remove harmful LDL cholesterol from the bloodstream. Even more promising from a clinical standpoint, the research team has identified an experimental drug that has already undergone early-stage safety testing in humans and could potentially interfere with this newly uncovered destructive process.
The findings, which represent a major step forward in cardiovascular research, have been published in the prestigious scientific journal Nature. They could ultimately open the door to an entirely new therapeutic approach for managing high cholesterol, offering renewed hope for patients who have found limited success with traditional regimens.
"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 senior author Alan Saltiel, PhD, a professor of medicine at the UC San Diego School of Medicine and director of the UC San Diego/UCLA Diabetes Research Center. "This new discovery explains a critical piece of that puzzle."
How the Liver Removes Bad Cholesterol
To understand the significance of the new discovery, it is necessary to examine the central role that the liver plays in controlling overall cholesterol homeostasis within the human body. The liver acts as the primary processing hub for circulating lipids, systematically removing cholesterol from the bloodstream so it can be chemically processed, broken down, and utilized by other vital tissues and systems throughout the body.
To accomplish this demanding physiological task, liver cells rely on specialized molecular structures known as LDL receptors. Strategically located on the outer surface of these cells, the receptors operate much like microscopic docking stations, actively capturing circulating LDL cholesterol from the blood and pulling it inside the cell for subsequent degradation and processing.
The sheer quantity of available receptors matters immensely to this filtration process. When liver cells maintain a high density of functional LDL receptors on their surfaces, they can successfully capture and clear significantly greater quantities of cholesterol from circulation. This principle underlies the mechanism of action for some of the most widely prescribed and effective cardiovascular medications available today, including statins and PCSK9 inhibitors. These pharmaceutical treatments are designed precisely to help maintain or increase the number of active receptors available to clear out harmful LDL cholesterol before it can contribute to arterial plaque accumulation.
Scientists Uncover a Hidden Cholesterol Pathway
Despite the efficacy of existing medications, the cellular mechanisms governing receptor depletion under poor dietary conditions remained obscure until now. Utilizing a series of sophisticated experiments involving both animal models and human cells, the research team at UC San Diego uncovered a previously unrecognized biological process that actively interferes with the liver’s capacity to clear cholesterol. Over time, this newly identified mechanism systematically reduces the total number of functional LDL receptors, making it progressively harder for the human body to keep blood cholesterol under control, regardless of other lifestyle factors.
The newly mapped process is initiated by a protein known as Ral, a signaling molecule that Dr. Saltiel had previously investigated in the context of fat cells. The research team discovered that consuming high amounts of dietary cholesterol triggers the activation of Ral, setting off a cascade of biochemical events that ultimately leads to the depletion of LDL receptors. As Ral activity increases within the cellular environment, fewer receptors remain available on the cell surface to capture and remove harmful cholesterol from the bloodstream, creating a dangerous backlog of lipids in the circulation.
Digging deeper into the molecular mechanics, the researchers identified another critical component of the pathway: an enzyme called cathepsin A, commonly referred to as CTSA. This specific enzyme plays a direct role in driving the destructive process responsible for the systematic loss of LDL receptors from liver cell surfaces.
When the scientists applied a small molecule inhibitor specifically designed to block the activity of CTSA, the resulting laboratory effects were dramatic and immediate. The LDL receptors demonstrated significantly enhanced stability, and levels of circulating LDL cholesterol dropped precipitously in the murine models.
This discovery carries profound clinical implications because the newly mapped biological pathway operates independently of the metabolic routes targeted by standard cholesterol-lowering medications. That distinct separation could eventually make it possible to develop targeted treatments specifically tailored for patients who fail to respond adequately to existing pharmaceutical interventions.
"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 Dr. Saltiel. "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."
A Previously Tested Drug Could Accelerate Treatment
In conventional biomedical research, identifying a novel biological target represents merely the opening chapter of a notoriously lengthy and expensive drug development pipeline. Investigators typically must spend years—and sometimes decades—identifying suitable chemical compounds, optimizing their molecular structures, and conducting preclinical evaluations to determine whether a novel therapy can be administered safely to human subjects.
In this rare and promising instance, however, the researchers may already possess a viable candidate positioned to bypass some of these early hurdles.
Records show that a drug specifically designed to inhibit CTSA had previously been developed by pharmaceutical researchers as an experimental treatment for heart failure. Although that particular clinical development program was eventually discontinued due to strategic corporate decisions rather than safety failures, the experimental medication had already successfully progressed through a Phase 1 clinical trial. During that initial phase, it was rigorously evaluated and demonstrated an acceptable safety profile in human subjects.
That earlier foundational work could provide the research team with an invaluable operational advantage. Rather than initiating drug development entirely from scratch, investigators believe that the existing CTSA inhibitor could potentially be repurposed and advanced directly into a Phase 2 clinical trial to investigate its efficacy and safety profile specifically against hypercholesterolemia.
While the scientific findings remain at a relatively early stage, and the experimental compound has not yet been formally proven to lower cholesterol levels in human patients, its prior clinical testing history could dramatically shorten the typical timeline required to determine whether this novel therapeutic strategy holds clinical utility.
"Luckily, there’s an experimental drug sitting on the shelf that’s already been shown to be safe in humans," said Dr. 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."
The comprehensive study was conducted by a multidisciplinary team of scientists. Co-authors include Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva, and Amit R. Majithia at UC San Diego; Priya Jaishankar, Pusu Yang, and Adam Renslo at the University of California, San Francisco; Linmeng Han and Peng Zhao at the University of Texas Health Science Center at San Antonio; and Philip L.S.M. Gordts at the University of Utah.
Financial support for the investigation was provided in part by grants from the National Institutes of Health, including awards P30DK063491, R01DK117551, R01DK128796, and R01DK135289, alongside an American Diabetes Association postdoctoral fellowship under grant 1-25-PDF-76.
