High cholesterol is a common health concern, and the standard advice is to take statins, monitor diet, and allow the body to eliminate “bad” cholesterol. However, this approach is not effective for everyone, particularly those with a genetic predisposition. Researchers are now investigating an alternative strategy: preventing cholesterol production in the first place. This new approach focuses on stopping the creation of cholesterol rather than removing it from the bloodstream.
A genetic condition affecting millions of people
Familial hypercholesterolemia (FH) is a genetic disorder that impairs the body’s ability to remove low-density lipoprotein (LDL) cholesterol from the bloodstream. Normally, the liver has receptors that act as docking stations, capturing cholesterol from the blood and breaking it down. In individuals with FH, a genetic mutation disrupts the functioning of these receptors, leading to a buildup of cholesterol in the blood. This can occur without noticeable symptoms, often resulting in a heart attack or other cardiovascular event. Approximately 1 in 200 adults carries this genetic mutation, making FH one of the most common inherited disorders worldwide.
Many people are unaware that they have this condition, which can have severe consequences if left untreated. The prevalence of FH is surprising, given its potential impact on cardiovascular health. The fact that so many people are affected by this genetic disorder highlights the need for alternative treatment approaches.
Statins have been the primary treatment for high cholesterol for decades and are effective for most people. However, they work by enhancing the activity of LDL receptors, which may be impaired or missing in individuals with FH. As a result, statins may not be sufficient for people with severe FH, particularly those who have inherited defective genes from both parents. This limitation has led researchers to explore new strategies for managing cholesterol levels.
Read Also: Millions with kidney disease go undiagnosed despite simple tests
A new target: The protein responsible for cholesterol particle formation
A research team at the Medical University of South Carolina has focused on Apolipoprotein B (ApoB), a protein that plays a key role in the formation of LDL particles. By targeting ApoB, researchers aim to reduce the amount of cholesterol released from the liver into the bloodstream. This approach does not rely on the faulty LDL receptors, offering a potential solution for individuals with FH. The team used a testing system based on induced pluripotent stem cells to screen potential compounds and identify those that can reduce ApoB and cholesterol levels.
Their research, published in Communications Biology, involved screening approximately 130,000 compounds from the South Carolina Compound Collection. The team identified a specific group of molecules that sharply reduced ApoB and cholesterol levels. According to Stephen Duncan, D.Phil., who led the study, their approach is “the original way of doing pharmacology—trying to find drugs that can fix the disease without knowing how it fixes it.” The team’s method involves modeling the disease first and then screening drugs to find which ones work, followed by retrospective analysis to understand how the drug functions.
In a 2026 study published in microPublication Biology, the researchers examined the effects of their lead compound, DL-1, on liver cells at the genetic level. Using RNA sequencing, they found that DL-1 caused limited changes in gene activity, affecting only 182 genes. The genes that decreased did not cluster into any major biological pathway, suggesting that DL-1 does not broadly disrupt normal liver function. The team also observed an increase in metallothionein genes, which help protect cells from stress, supporting the idea that DL-1 interferes with ApoB processing and release rather than shutting down the ApoB gene itself.
Implications for treatment and future research
For most people, the current approach to managing cholesterol, including lifestyle changes, statins, and regular check-ins with a doctor, remains effective. However, for individuals with FH, especially those with severe forms, this research offers a new path forward. By targeting cholesterol production at its source, rather than relying on a potentially broken cleanup system, scientists may be able to develop more effective treatments for this genetic disorder.