Forget Clearing Cholesterol—What If We Just Stopped Making It?

If you've ever been told your cholesterol is too high, you've probably heard the same advice: take a statin, watch your diet, and let your body do the work of clearing out the "bad" cholesterol.

For some people, that approach works fine. But for millions of others, it doesn't, and the reason comes down to genetics.

Familial hypercholesterolemia (FH) is one of those conditions that often flies under the radar. It's a genetic disorder that disrupts the body's ability to clear LDL cholesterol—the kind that can build up in your arteries over time.

Here's how it normally works: Your liver has LDL receptors that act like tiny docking stations. They grab cholesterol from your bloodstream and pull it into cells, where it gets broken down. Simple enough.

But in people with FH, a genetic mutation that disrupts how these receptors work means the docking stations don't work properly—or don't work at all. Cholesterol accumulates in the blood for years, often without any obvious symptoms, until it shows up as a heart attack or other cardiovascular event.

Statins have been the gold standard for lowering cholesterol for decades, and they're genuinely effective for most people. But here's the catch: they work by boosting LDL receptor activity.

If your receptors are already impaired—or essentially missing—statins can only do so much. For people with severe FH, especially those who inherited defective genes from both parents, traditional treatments often fall short.

A research team at the Medical University of South Carolina (MUSC) decided to focus on something called Apolipoprotein B, or ApoB for short. Think of ApoB as the scaffolding that holds LDL particles together. Without it, cholesterol-carrying particles can't form properly in the first place.

Basically, instead of trying to clear cholesterol that's already circulating in your blood, reduce how much gets released from the liver to begin with. And importantly, this approach doesn't depend on those faulty LDL receptors at all.

Their work, published in Communications Biology1, used a testing system built from induced pluripotent stem cells (iPSCs). In plain terms, they took adult cells—like skin or blood cells—and reprogrammed them to become liver-like cells in the lab. This gave them a way to test potential drugs on something that actually behaves like a human liver, which matters because cholesterol metabolism works differently in mice than in people.

Using their human-like liver cell system, the researchers screened about 130,000 compounds from the South Carolina Compound Collection. A specific group of molecules stood out: they sharply reduced the release of ApoB, along with cholesterol and triglyceride 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." He explained that by modeling the disease first, researchers can screen drugs to find which ones work, then figure out retrospectively how the drug functions.

When the team tested these compounds in regular mice, they didn't see much effect. But that wasn't because the compounds failed—it was because mouse livers just don't respond the same way human livers do.

The team continued their work in a 2026 study published in microPublication Biology, examining how their lead compound (called DL-1) affects liver cells at the genetic level.

Using RNA sequencing, they found that DL-1 caused relatively limited changes in gene activity—only 182 genes were significantly affected. More importantly, the genes that decreased didn't cluster into any major biological pathway, suggesting the compound doesn't broadly disrupt normal liver function.

Let's be clear: these compounds aren't available as treatments yet. There's still work to be done to understand exactly how they function at a molecular level and to confirm their long-term safety. Researchers are also exploring how they might work alongside existing therapies.

For most of us, the current playbook for managing cholesterol—lifestyle changes, statins when needed, regular check-ins with your doctor—remains the right approach.