Two La Jolla research teams are zeroing in on cholesterol from two very different angles, and both could eventually reshape how doctors tackle high LDL and certain cancers. One group at UC San Diego has mapped a liver pathway that speeds up the destruction of LDL receptors, while another at Sanford Burnham Prebys has shown how tumor cells reroute cholesterol to fuel their own growth. Together, the findings spotlight drug targets, including an experimental compound that has already cleared Phase 1 safety testing in humans.
UC San Diego Maps a Hidden Liver Pathway
The UC San Diego-led study uncovers a Ral-dependent route in the liver that sends LDL receptors into lysosomes, where the enzyme cathepsin A (CTSA) helps break them down. That mechanism helps explain why long-term high-cholesterol diets can blunt the liver's ability to clear LDL from the blood. In mice and human cells, the team showed that blocking CTSA with a small-molecule inhibitor stabilized LDL receptors and sharply reduced circulating LDL cholesterol. The work outlines a potential treatment strategy that focuses on preserving LDL receptors rather than boosting their production or targeting circulating regulators, as reported in Nature.
A Drug Already on the Shelf
Conveniently for the researchers, a CTSA inhibitor has already made it through early-stage human testing after being developed for heart failure. That could shorten the runway from lab discovery to clinical trials in people with high cholesterol. "Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans," said Alan Saltiel, the study's senior author. Because the compound has passed Phase 1 safety testing, Saltiel and colleagues say it is a candidate for rapid evaluation in trials aimed at cholesterol control, according to UC San Diego.
Targeting Cholesterol Trafficking in Tumors
Across town at Sanford Burnham Prebys, researchers led by Brooke Emerling homed in on how certain cancers lean on cholesterol to keep growing. The team found that phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) are needed to position cholesterol-packed lysosomes near the cell membrane in TP53-mutant cancers, which in turn supports mTORC1-driven growth. When the scientists deleted or inhibited those kinases in mice, tumors failed to develop, revealing a vulnerability in cancers that overproduce cholesterol. The findings lay out a way to "starve" tumors by disrupting intracellular cholesterol transport, as detailed in Science Advances.
Different Problems, Related Solutions
Although the two studies tackle different problems, they share a common theme: what happens to cholesterol inside cells can matter as much as the cholesterol reading on a blood test. One approach aims to preserve LDL receptors in the liver to pull more LDL out of circulation. The other aims to scramble cholesterol trafficking inside cancer cells so that key growth signals are cut off. Experts caution that these are early-stage results. The mouse and cell data still need to be translated into human trials before anyone can claim a clinical benefit, as discussed by The Scientist.
La Jolla's Research Engine
The tandem papers also highlight La Jolla's unusually dense biomedical ecosystem. UC San Diego and Sanford Burnham Prebys led the mechanistic work, teaming up with collaborators at UCSF, UT Health San Antonio and the University of Utah. Local coverage notes that the projects were coordinated from La Jolla labs and could ultimately feed into nearby clinical trials or biotech spinouts that keep the next phase of development close to home, according to The San Diego Union-Tribune.
What Comes Next
For now, researchers stress that passing a Phase 1 safety study is only a starting point. Larger, controlled trials will be needed to find out whether a CTSA inhibitor can actually reduce cardiovascular risk in the way statins or PCSK9 inhibitors do. Even so, the new work lays out a relatively clear translational path: a mechanism that links CTSA to LDL receptor loss, an existing small molecule ready for further testing in LDL control, and a fresh enzyme class to pursue in cholesterol-hungry tumors. That roadmap could speed follow-up studies and eventually lead to patient-facing trials, according to UC San Diego.
