CTSB promotes ferroptosis in macrophage-derived foam cells and aggravates plaque instability via the NRF2/HMOX1 axis.

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid accumulation and plaque formation, representing a leading cause of life-threatening cardiovascular events. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been implicated in atherosclerotic progression; however, the exact mechanism remains elusive. Here, we identified cathepsin B (CTSB) as a novel ferroptosis-related gene through bioinformatic screening and investigated its functional role in macrophage-derived foam cells and plaque instability using both in vitro and in vivo models. Mechanistically, CTSB bound to and stabilized nuclear factor erythroid 2-related factor 2 (NRF2), facilitating its nuclear translocation and subsequent transcriptional activation of heme oxygenase-1 (HMOX1), a pivotal regulator of iron homeostasis and oxidative stress. Consequently, CTSB-driven HMOX1 upregulation promoted ferroptosis and exacerbated plaque vulnerability, whereas CTSB knockdown or pharmacological inhibition reversed these effects. Collectively, our findings uncover a CTSB/NRF2/HMOX1 signaling cascade that drives ferroptosis in macrophage-derived foam cells and promotes plaque instability, positioning CTSB as a promising therapeutic target for stabilizing high-risk atherosclerotic plaques.