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

Xiang Peng; Bin Sun; Chaohui Tang; Chengyu Shi; Xianwei Xie; Xueyu Wang; Dingsheng Jiang; Shuo Li; Ying Jia; Yani Wang; Huifang Tang; Shan Zhong; Minghui Piao; Xiuru Cui; Shenghao Zhang; Fan Wang; Yan Wang; Ruisi Na; Renping Huang; Yanan Jiang; Weihua Zhang; Juan Xu; Kaiyang Lin; Junli Guo; Zhenwei Pan; Kun Wang; Qiang Zhao; Huibin Liu; Bo Yu; Yong Ji; Jian Zhang; Shuijie Li; Jinwei Tian

doi:10.1016/j.devcel.2024.12.011

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

Dev Cell. 2024 Dec 18:S1534-5807(24)00733-0. doi: 10.1016/j.devcel.2024.12.011. Online ahead of print.

Authors

Xiang Peng¹, Bin Sun², Chaohui Tang¹, Chengyu Shi¹, Xianwei Xie³, Xueyu Wang¹, Dingsheng Jiang⁴, Shuo Li³, Ying Jia⁵, Yani Wang⁶, Huifang Tang⁷, Shan Zhong¹, Minghui Piao¹, Xiuru Cui¹, Shenghao Zhang¹, Fan Wang³, Yan Wang³, Ruisi Na⁸, Renping Huang⁹, Yanan Jiang¹⁰, Weihua Zhang¹¹, Juan Xu¹², Kaiyang Lin¹³, Junli Guo¹⁴, Zhenwei Pan¹⁰, Kun Wang¹⁵, Qiang Zhao¹⁶, Huibin Liu¹⁷, Bo Yu¹⁸, Yong Ji¹⁹, Jian Zhang²⁰, Shuijie Li²¹, Jinwei Tian²²

Affiliations

¹ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin 150086, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150081, China.
² College of Pharmacy, Harbin Medical University, Harbin 150081, China.
³ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin 150086, China.
⁴ Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁵ Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
⁶ State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150080, China.
⁷ Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang 421001, China.
⁸ College of Pharmacy, Harbin Medical University, Harbin 150081, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150080, China; Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti-Tumor Drugs, Harbin 150081, China.
⁹ Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
¹⁰ College of Pharmacy, Harbin Medical University, Harbin 150081, China; State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin 150081, China.
¹¹ Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
¹² College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
¹³ Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China.
¹⁴ Key Laboratory of Emergency and Trauma of Ministry of Education, Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences, Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China.
¹⁵ Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266003, China.
¹⁶ State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China.
¹⁷ Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin 150086, China; Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
¹⁸ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150081, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150080, China. Electronic address: [email protected].
¹⁹ College of Pharmacy, Harbin Medical University, Harbin 150081, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150080, China. Electronic address: [email protected].
²⁰ School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: [email protected].
²¹ College of Pharmacy, Harbin Medical University, Harbin 150081, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150080, China; Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti-Tumor Drugs, Harbin 150081, China. Electronic address: [email protected].
²² Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin 150086, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150081, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin 150080, China. Electronic address: [email protected].

PMID: 39731912
DOI: 10.1016/j.devcel.2024.12.011

Abstract

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^low) 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.

Keywords: LDHB; TREM2(low) foamy macrophages; advanced atherosclerosis; ferroptosis; mitochondrial dysfunction.