Scientists Discover Game-Changing New Way To Treat High Cholesterol

Scientists are exploring a new way to treat familial hypercholesterolemia.

Scientists are rethinking how to treat a widespread genetic cholesterol disorder by targeting particle production instead of removal.

Familial hypercholesterolemia (FH) disrupts one of the body’s most important cleanup systems. Normally, low-density lipoprotein (LDL), often called “bad” cholesterol, is removed from the bloodstream by LDL receptors (LDLR) in the liver. These receptors act like docking stations, pulling cholesterol into cells where it can be broken down. In people with FH, mutations in the LDLR gene weaken or disable this process.

As a result, cholesterol builds up in the blood for decades, often without obvious symptoms until it leads to heart attacks or other cardiovascular problems. About 1 in 200 adults carries this genetic change, making it one of the most common inherited disorders worldwide.

Some researchers have even suggested that familial hypercholesterolemia may have appeared in historical art. Subtle features in Leonardo da Vinci’s Mona Lisa, for example, have been interpreted as possible xanthomas—fatty deposits under the skin that can signal the disorder.

Rethinking Cholesterol Treatment

While statins have been the standard treatment for lowering cholesterol, they rely on boosting LDLR activity. This creates a significant limitation. In patients whose receptors are severely impaired or absent, especially those with two defective gene copies, statins may have little effect. This limitation has prompted researchers to rethink the problem entirely. Instead of enhancing cholesterol removal, what if therapies could reduce how much cholesterol is produced and released in the first place?

A research team at the Medical University of South Carolina (MUSC) has taken that approach. Their work, published in Communications Biology, focuses on apolipoprotein B (apoB), a protein that acts as the structural backbone of LDL particles. Without apoB, these cholesterol-carrying particles cannot form properly. Targeting apoB offers a way to lower the number of LDL particles circulating in the blood, independent of the LDL receptor pathway.

Building a Human-Like Testing System

To search for compounds that could do this, the team turned to induced pluripotent stem cells (iPSCs). These cells are created by reprogramming adult skin or blood cells into a flexible, stem-like state, then guiding them to become liver-like cells in the lab.

This allowed the researchers to build a testing system that closely mimics human liver function, an important step because cholesterol metabolism varies significantly between species.

Using this platform, they screened the South Carolina Compound Collection (SC3), a library of about 130,000 compounds. The results stood out. A specific group of molecules sharply reduced the release of apoB, along with drops in cholesterol and triglyceride levels inside the cells.

“Our approach is the original way of doing pharmacology – trying to find drugs that can fix the disease without knowing how it fixes it,” said Stephen Duncan, D.Phil., who led the study. “You model the disease, and then you can screen drugs to find out which ones work. Then you can work out retrospectively how the drug functions.”

“The nice thing about that is you are starting off by knowing the drug can actually fix the problem you hope to fix,” he added.

Overcoming the Animal Model Gap

When the team moved to traditional mouse testing, the progress stalled. The compounds showed little effect, not because they failed outright, but because mouse liver cells responded differently than human cells.

To bridge that gap, the researchers used “Avatar” mice developed with Yecuris. These mice are engineered to carry human liver cells, effectively giving them a human-like cholesterol system.

“We used a humanized mouse model – a mouse with ‘your’ liver in it,” explained Duncan.

In these humanized mice, the compounds worked as expected, lowering lipid levels in a way that mirrors human biology. This step is critical because it provides stronger evidence that the findings could translate into real treatments.

What makes these compounds especially intriguing is that they bypass the LDL receptor entirely. That opens the door for patients who have few options today.

A Shift Toward Targeting Disease Mechanisms

By combining stem cell technology with large-scale compound screening, scientists can now test therapies directly on human-like systems early in development. This reduces reliance on imperfect animal models and may improve the odds of finding treatments that actually work in patients.

“Showing that you can use these human stem cells as a system to model disease, complete a drug discovery process and find a drug that could potentially be used to treat a patient – that is the epitome of personalized medicine,” said Duncan. “This shows there is a very feasible way to do drug discovery using a human system.”

There is still more to learn. Researchers need to identify exactly how these compounds work at a molecular level and determine their long-term safety. Another key question is how they might pair with existing treatments. Combining therapies that reduce both the creation of LDL particles and their removal from the bloodstream could offer a more complete solution.

Follow-up research is already beginning to answer some of those questions. In a 2026 study published in microPublication Biology, the team examined how their lead compound, DL-1, affects liver cells at the genetic level. Using RNA sequencing, they found that the treatment caused relatively limited changes in gene activity, with 182 genes significantly affected. Notably, the genes that were reduced did not group into any major biological pathway, suggesting the compound does not broadly disrupt normal liver function.

The researchers also observed an increase in several metallothionein genes, which help regulate metals and protect cells from stress. This pattern may be linked to the compound’s thiol structure interacting with metal ions inside cells. Together, these findings support earlier evidence that DL-1 does not lower ApoB by shutting down its gene, but instead likely interferes with how the protein is processed and released.

References:

“A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B” by Jui-Tung Liu, Caren Doueiry, Yu-lin Jiang, Josef Blaszkiewicz, Mary Paige Lamprecht, James A. Heslop, Yuri K. Peterson, Juliana Debrito Carten, Paula Traktman, Yang Yuan, Salman R. Khetani, Waleed O. Twal and Stephen A. Duncan, 24 April 2023, Communications Biology.
DOI: 10.1038/s42003-023-04739-9

“Effect of triazine thiols on steady-state mRNA levels in iPSC-derived hepatocytes” by Carla Martinez-Morant, Jui-Tung Liu, Yu-Lin Jiang, Josef Blaszkiewicz and Stephen A Duncan, 6 March 2026, microPublication Biology.
DOI: 10.17912/micropub.biology.002062

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