Cathepsin C promotes atherosclerosis by modulating neutrophil recruitment and neutrophil extracellular trap formation.

Atherosclerotic plaque instability is a critical determinant of sudden cardiac death (SCD). While Cathepsin C (CTSC) participates in inflammatory diseases, its functional contribution and cellular origin in atherosclerosis remain incompletely understood. This study investigates whether CTSC derived from foam cells modulates neutrophil behavior to exacerbate plaque progression. We analyzed human coronary arteries from control, coronary heart disease (CHD), and SCD cohorts. An ApoE-/- mouse model of atherosclerosis with AAV-mediated CTSC knockdown was established. Cellular experiments involved co-culture of THP-1-derived foam cells with differentiated HL-60 neutrophils, employing the CTSC inhibitor AZD7986 for mechanistic studies. We found that CTSC and neutrophil extracellular trap (NETs) markers were significantly elevated in human and mouse plaques and were particularly increased in SCD specimens. Silencing CTSC in mice markedly attenuated plaque development and NETS formation. Mechanistically, foam cell-secreted CTSC promoted neutrophil migration by activating the PR3/IL-1β/NF-κB signaling cascade. Simultaneously, CTSC triggered NETosis through a separate p38 MAPK/ROS-dependent pathway. Notably, the resulting NETs enhanced lipid accumulation in foam cells, creating a pathogenic feedback cycle. Our findings identify CTSC as an important regulator of neutrophil recruitment and NETosis in atherosclerosis and suggest its potential as a therapeutic target for plaque stabilization. Our findings identify CTSC as an important regulator of neutrophil recruitment and NETosis in atherosclerosis and suggest its potential as a therapeutic target for modulating atherosclerotic plaque pathology.