Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis

Siting Zhang, Hui Lin, Jiale Wang, Jingyu Rui, Tengwei Wang, Zeyu Cai, Shenming Huang, Yanxiang Gao, Tianfeng Ma, Rui Fan, Rongbo Dai, Zhiqing Li, Yiting Jia, Qiang Chen, HaoMing He, Jiaai Tan, Shirong Zhu, Rui Gu, Zhigang Dong, Meihong Li, Enmin Xie, Yi Fu, Jingang Zheng (), Changtao Jiang (), Jinpeng Sun () and Wei Kong ()
Additional contact information
Siting Zhang: Peking University Health Science Center
Hui Lin: Shandong University
Jiale Wang: Peking University Health Science Center
Jingyu Rui: Peking University Health Science Center
Tengwei Wang: Shandong University
Zeyu Cai: Peking University Health Science Center
Shenming Huang: Shandong University
Yanxiang Gao: Peking University China–Japan Friendship School of Clinical Medicine
Tianfeng Ma: Chinese PLA General Hospital
Rui Fan: Peking University Health Science Center
Rongbo Dai: Peking University Health Science Center
Zhiqing Li: Peking University Health Science Center
Yiting Jia: Peking University Health Science Center
Qiang Chen: Peking University China–Japan Friendship School of Clinical Medicine
HaoMing He: Peking University China–Japan Friendship School of Clinical Medicine
Jiaai Tan: Peking University Health Science Center
Shirong Zhu: Peking University Health Science Center
Rui Gu: Peking University Health Science Center
Zhigang Dong: Peking University Health Science Center
Meihong Li: Peking University Health Science Center
Enmin Xie: Peking University China–Japan Friendship School of Clinical Medicine
Yi Fu: Peking University Health Science Center
Jingang Zheng: Peking University China–Japan Friendship School of Clinical Medicine
Changtao Jiang: Peking University Health Science Center
Jinpeng Sun: Peking University
Wei Kong: Peking University Health Science Center

Nature, 2025, vol. 641, issue 8062, 476-485

Abstract: Abstract Recent evidence has shown that increased levels of circulating long-chain ceramides predict atherosclerotic cardiovascular disease independently of cholesterol1,2. Although targeting ceramide signalling may provide therapeutic benefits beyond the treatment of hypercholesterolaemia, the underlying mechanism by which circulating ceramides aggravate atherosclerotic cardiovascular disease remains elusive. Here we examine whether circulating long-chain ceramides activate membrane G-protein-coupled receptors to exacerbate atherosclerosis. We perform a systematic screen that combines G-protein-signalling quantification, bioinformatic analysis of G-protein-coupled receptor expression and functional examination of NLRP3 inflammasome activation. The results suggest that CYSLTR2 and P2RY6 are potential endogenous receptors of C16:0 ceramide-induced inflammasome activation in both endothelial cells and macrophages. Inhibition of CYSLTR2 and P2RY6 genetically or pharmacologically alleviates ceramide-induced atherosclerosis aggravation. Moreover, increased ceramide levels correlate with the severity of coronary artery disease in patients with varying degrees of renal impairment. Notably, CYSLTR2 and P2RY6 deficiency mitigates chronic-kidney-disease-aggravated atherosclerosis in mice without affecting cholesterol or ceramide levels. Structural analyses of ceramide–CYSLTR2–Gq complexes reveal that both C16:0 and C20:0 ceramides bind in an inclined channel-like ligand-binding pocket on CYSLTR2. We further reveal an unconventional mechanism underlying ceramide-induced CYSLTR2 activation and the CYSLTR2–Gq interface. Overall, our study provides structural and molecular mechanisms of how long-chain ceramides initiate transmembrane Gq and inflammasome signalling through direct binding to CYSLTR2 and P2RY6 receptors. Therefore, blocking these signals may provide a new therapeutic potential to treat atherosclerosis-related diseases.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08792-8 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:641:y:2025:i:8062:d:10.1038_s41586-025-08792-8

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08792-8

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().