The hepatic low-density lipoprotein receptor (LDLR) mediates the clearance of circulating low-density lipoprotein (LDL) and is a key determinant of cholesterol homeostasis. However, how nutritional cues such as chronic dietary cholesterol regulate LDLR intracellular trafficking and protein turnover through specific molecular switches remains poorly understood. Dr. Alan Saltiel’s team at the University of California San Diego discovered a cholesterol stress-response pathway mediated by Ral GTPases, revealing a new mechanism by which dietary cholesterol reshapes LDLR protein fate and thereby affects cholesterol homeostasis. The study found that chronic dietary cholesterol loading or sustained Ral activation reduces LDLR protein levels. Mechanistically, chronic cholesterol loading activates Ral GTPases by increasing RAS activity. Activated Ral, on the one hand, recruits the RalBP1-REPS1 endocytic complex to promote LDLR internalization and lysosomal trafficking while inhibiting LDLR recycling back to the cell surface. On the other hand, Ral activation promotes the processing and lysosomal localization of cathepsin A (CTSA) and reduces its extracellular secretion, thereby enhancing CTSA-mediated LDLR degradation. This process occurs independently of LDLR transcriptional regulation or PCSK9-mediated LDLR degradation. Inhibition of CTSA stabilizes LDLR protein and promotes LDL uptake and plasma cholesterol clearance. Human genetic analyses further indicate that key components of this pathway are associated with plasma lipid levels and cardiovascular disease risk. This study reveals a dietary cholesterol-activated Ral-CTSA-LDLR protein homeostasis pathway, providing a new mechanistic framework for understanding how nutritional stress disrupts cholesterol metabolism and identifying a potential therapeutic target distinct from existing treatment strategies for hypercholesterolemia and cardiovascular disease.