Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

Yiting Jia; Lu Zhang; Ziyi Liu; Chenfeng Mao; Zihan Ma; Wenqiang Li; Fang Yu; Yingbao Wang; Yaqian Huang; Weizhen Zhang; Jingang Zheng; Xian Wang; Qingbo Xu; Jian Zhang; Wei Feng; Caihong Yun; Chuanju Liu; Jinpeng Sun; Yi Fu; Qinghua Cui; Wei Kong

doi:10.1038/s41421-021-00363-1

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

Cell Discov. 2022 Mar 1;8(1):21. doi: 10.1038/s41421-021-00363-1.

Authors

Yiting Jia^#¹, Lu Zhang^#^{1

2}, Ziyi Liu^#¹, Chenfeng Mao¹, Zihan Ma¹, Wenqiang Li¹, Fang Yu¹, Yingbao Wang¹, Yaqian Huang¹, Weizhen Zhang¹, Jingang Zheng³, Xian Wang¹, Qingbo Xu⁴, Jian Zhang⁵, Wei Feng⁶, Caihong Yun⁷, Chuanju Liu^{8

9}, Jinpeng Sun¹, Yi Fu¹, Qinghua Cui¹⁰, Wei Kong¹¹

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
² The Affiliated Hospital of Qingdao University, Qingdao, China.
³ Department of Cardiology, China-Japan Friendship Hospital, Beijing, China.
⁴ Cardiovascular Division, Kings College London BHF Centre, London, SE5 9NU, UK.
⁵ State Key Laboratory of Oncogenes and Related Genes, Medicinal Chemistry & Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁷ Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
⁸ Department of Orthopedic Surgery, New York University Medical Center, New York, NY, USA.
⁹ Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
¹⁰ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China. cuiqinghua@bjmu.edu.cn.
¹¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China. kongw@bjmu.edu.cn.

^# Contributed equally.

Abstract

Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO₄)-induced C57BL/6J mice and angiotensin II-infused ApoE^-/- mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.

Abstract

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