Scientists discover a hidden driver of high cholesterol and a way to stop it

Key Points:

• Researchers at UC San Diego School of Medicine have identified a new biological pathway explaining how high-cholesterol diets reduce the liver's ability to remove harmful LDL cholesterol, involving activation of the protein Ral and the enzyme cathepsin A (CTSA).
• This pathway leads to a decrease in LDL receptors on liver cells, impairing cholesterol clearance, and is distinct from mechanisms targeted by current cholesterol medications like statins and PCSK9 inhibitors.
• Blocking CTSA with a small molecule inhibitor in mice stabilized LDL receptors and significantly lowered circulating LDL cholesterol, suggesting a potential new therapeutic target for high cholesterol.
• An experimental CTSA inhibitor drug, previously tested for safety in humans during a Phase 1 trial for heart failure, could be repurposed and advanced to Phase 2 trials for cholesterol treatment, potentially accelerating drug development.
• The findings offer hope for new cholesterol-lowering options, particularly for patients who do not respond adequately to existing therapies, though human efficacy remains to be demonstrated.