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ResearchIn-Press PreviewCardiologyMetabolism Open Access | 10.1172/JCI186509

E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1

Lei Cao,1 Jie Zhang,1 Liwen Yu,1 Wei Yang,1 Wenqian Qi,1 Ruiqing Ren,1 Yapeng Liu,1 Yonghao Hou,1 Yu Cao,1 Qian Li,1 Xiaohong Wang,1 Zhengguo zhang,2 Bo Li,3 Wenhai Sui,1 Yun Zhang,1 Chengjiang Gao,4 Cheng Zhang,1 and Meng Zhang1

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Cao, L. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Zhang, J. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Yu, L. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Yang, W. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Qi, W. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Ren, R. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Liu, Y. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Hou, Y. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Cao, Y. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Li, Q. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Wang, X. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by zhang, Z. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Li, B. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Sui, W. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Zhang, Y. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Gao, C. in: PubMed | Google Scholar |

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Zhang, C. in: PubMed | Google Scholar

1State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

2Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China

3Department of Cardiology, Zibo Central Hospital, Zibo, China

4Key Laboratory of Infection and Immunity of Shandong Province, Department o, Cheeloo College of Medicine, Shandong University, Jinan, China

Find articles by Zhang, M. in: PubMed | Google Scholar

Published June 17, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186509.
Copyright © 2025, Cao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 17, 2025 - Version history
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Abstract

Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.

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