HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis by Xiang Peng, Bin Sun, Chaohui Tang, ..., ISBN 101016/JDEVCEL202412011 instant download

HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis by Xiang Peng, Bin Sun, Chaohui Tang, ..., ISBN 101016/JDEVCEL202412011 instant download

SUMMARYAdvanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residualrisk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a maincontributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNAsequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamymacrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2(TREM2low) 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. Administrationof the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targetedTEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamymacrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.1070 Developmental Cell 60, 1070–1086, April 7, 2025 ª 2024 Elsevier Inc.All rights are reserved, including those for text and data mining, AI training, and similar technologies.