HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis.

Advanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residual risk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a main contributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNA sequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamy macrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2 (TREM2) foamy macrophages. This cluster exhibits metabolic characteristics with low oxidative phosphorylation (OXPHOS), increasing ferroptosis sensitivity. Mechanically, upregulated heme oxygenase 1 (HMOX1)-lactate dehydrogenase B (LDHB) interaction enables Lon peptidase 1 (LONP1) to degrade mitochondrial transcription factor A (TFAM), leading to mitochondrial dysfunction and ferroptosis. Administration of the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targeted TEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamy macrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.