Cathepsin L activates Notch1 through direct proteolytic cleavage rather than conventional ligand binding, triggering a cascade that accelerates endothelial cell senescence and atherosclerotic plaque formation. This non-canonical pathway represents a distinct mechanistic target for senescence-related cardiovascular disease.
Key Points
- Cathepsin L directly cleaves Notch1, bypassing ligand-dependent activation
- Activated Notch1 induces CUX1/p16-dependent senescence in endothelial cells
- Blocking CUX1 reduces atherosclerotic lesions and preserves plaque structure
Longevity Analysis
The identification of cathepsin L as a ligand-independent Notch1 activator reveals how proteolytic activity in the detoxification and defense systems can paradoxically accelerate cellular aging when dysregulated. Endothelial senescence is not merely a marker of atherosclerosis but a driver of plaque instability and vascular dysfunction. Targeting this pathway addresses a root mechanism of age-related cardiovascular decline rather than treating downstream inflammation or lipid accumulation alone.
Original published by Wiley Aging Cell, by Yuwei Wu, Lili Lu, Shaoyang Yan, Zewen Du, Danli Jiang, Ting Wu, Qichao Wu, Jie Liu, Johny Ebin, Wei Sun, Partha Dutta, Jay Xiaojun Tan, Jonathan K. Alder, Gang Li .