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Researchers at UC San Diego have uncovered a hidden mechanism that explains why high-cholesterol diets gradually impair the liver's ability to clear LDL from the bloodstream. The culprit? A protein called Ral and an enzyme called cathepsin A (CTSA). Blocking CTSA with an experimental drug dramatically lowered LDL in mice — and that drug has already passed a human safety trial, potentially fast-tracking a new cholesterol treatment.
Researchers at UC San Diego School of Medicine have identified a previously unknown biological pathway that explains why high-cholesterol diets progressively weaken the liver's ability to remove harmful LDL cholesterol from the blood. The findings, published in Nature, could pave the way for an entirely new class of cholesterol-lowering treatments.
The mechanism centers on a protein called Ral, which gets activated by high dietary cholesterol intake. Ral triggers a chain reaction involving an enzyme called cathepsin A (CTSA), which depletes the LDL receptors on liver cells responsible for clearing cholesterol from circulation. Fewer receptors mean more LDL stays in the blood — a key driver of heart disease risk. When scientists blocked CTSA using a small molecule inhibitor, LDL receptor levels stabilized and circulating LDL dropped dramatically in mice. Crucially, this pathway is entirely distinct from those targeted by statins or PCSK9 inhibitors, meaning it could help patients who don't respond to existing therapies.
Key Takeaways:
Why it matters: Millions of patients still can't reach safe cholesterol levels despite current medications. This discovery opens a new therapeutic avenue — and with a safety-tested drug candidate already in hand, a Phase 2 trial could arrive sooner than expected.
