The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis
Abstract Introduction Gasdermin D (GSDMD) and the pyroptosis it mediates are importantly involved in cardiovascular diseases (CVDs). Identifying and developing new inhibitors of GSDMD could be a promising strategy for treating pyroptosis‐mediated diseases, such as atherosclerosis. Objectives We aime...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-03-01
|
| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.70263 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850271259355512832 |
|---|---|
| author | Xiaoxi Fan Zhenfeng Cheng Ruiyin Shao Keke Ye Xudong Chen Xueli Cai Shanshan Dai Zhixuan Tang Si Shi Wenyuan Zheng Weijian Huang Jibo Han Bozhi Ye |
| author_facet | Xiaoxi Fan Zhenfeng Cheng Ruiyin Shao Keke Ye Xudong Chen Xueli Cai Shanshan Dai Zhixuan Tang Si Shi Wenyuan Zheng Weijian Huang Jibo Han Bozhi Ye |
| author_sort | Xiaoxi Fan |
| collection | DOAJ |
| description | Abstract Introduction Gasdermin D (GSDMD) and the pyroptosis it mediates are importantly involved in cardiovascular diseases (CVDs). Identifying and developing new inhibitors of GSDMD could be a promising strategy for treating pyroptosis‐mediated diseases, such as atherosclerosis. Objectives We aimed to develop new inhibitor of GSDMD in atherosclerosis, as well as clarify the mechanisms underlying this inhibiting effect. Methods Surface plasmon resonance and pull‐down assay were used to identify the amino acid sites of GSDMD inhibited by GI‐Y2. A mouse model of atherosclerosis was established by feeding a high‐fat diet for 12 weeks. After treating mice with GI‐Y2 (10 or 20 mg/kg, i.g.), the lipid plaque area on the arterial intimal surface, lipid deposition, collagen deposition and pyroptosis levels in aortic root sections were evaluated. Additionally, further treatment of atherosclerotic mice with macrophage membrane‐encapsulated GI‐Y2 was conducted to enhance the targeting ability of GI‐Y2 to atherosclerotic plaques. Results In this study, we confirmed GI‐Y2 as a novel inhibitor of GSDMD via structure‐based virtual screening and pharmacological validation. Mechanistically, GI‐Y2 directly interacts with the Arg10 residue of GSDMD and reduces the membrane binding of GSDMD‐N. Functionally, we revealed that GI‐Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD. Similarly, GI‐Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis. Furthermore, we constructed macrophage membrane‐coated GI‐Y2 nanoparticles to enhance the targeting of GI‐Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo. Conclusion This work demonstrated that GI‐Y2 can potentially alleviate CVDs by targeting GSDMD and provided a new compound for the study of GSDMD‐mediated pyroptosis. Key points We preliminarily confirmed GI‐Y2 as a novel inhibitor of GSDMD via structure‐based virtual screening and pharmacological validation. GI‐Y2 directly interacts with GSDMD and reduces the membrane binding of GSDMD‐N via the Arg10 residue. GI‐Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD and GI‐Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis. We constructed macrophage membrane‐coated GI‐Y2 nanoparticles to enhance the targeting of GI‐Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo. |
| format | Article |
| id | doaj-art-4fa189396eef4f25a3a4bc334736b9aa |
| institution | OA Journals |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-4fa189396eef4f25a3a4bc334736b9aa2025-08-20T01:52:18ZengWileyClinical and Translational Medicine2001-13262025-03-01153n/an/a10.1002/ctm2.70263The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosisXiaoxi Fan0Zhenfeng Cheng1Ruiyin Shao2Keke Ye3Xudong Chen4Xueli Cai5Shanshan Dai6Zhixuan Tang7Si Shi8Wenyuan Zheng9Weijian Huang10Jibo Han11Bozhi Ye12Department of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaHuzhou Central Hospital Affiliated Central Hospital of Huzhou University Huzhou ChinaDepartment of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaDepartment of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaDepartment of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaDepartment of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaThe Key Laboratory of Emergency and Disaster Medicine of Wenzhou Department of Emergency The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang ChinaFirst School of Medicine Wenzhou Medical University Wenzhou Zhejiang ChinaFirst School of Medicine Wenzhou Medical University Wenzhou Zhejiang ChinaKey Laboratory of Precision Medicine For Atherosclerosis Disease of Zhejiang Province Department of Cardiology Affiliated First Hospital of Ningbo University Ningbo Zhejiang ChinaDepartment of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaDepartment of Cardiology The Second Affiliated Hospital of Jiaxing University Jiaxing Zhejiang ChinaDepartment of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou the First Affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang ChinaAbstract Introduction Gasdermin D (GSDMD) and the pyroptosis it mediates are importantly involved in cardiovascular diseases (CVDs). Identifying and developing new inhibitors of GSDMD could be a promising strategy for treating pyroptosis‐mediated diseases, such as atherosclerosis. Objectives We aimed to develop new inhibitor of GSDMD in atherosclerosis, as well as clarify the mechanisms underlying this inhibiting effect. Methods Surface plasmon resonance and pull‐down assay were used to identify the amino acid sites of GSDMD inhibited by GI‐Y2. A mouse model of atherosclerosis was established by feeding a high‐fat diet for 12 weeks. After treating mice with GI‐Y2 (10 or 20 mg/kg, i.g.), the lipid plaque area on the arterial intimal surface, lipid deposition, collagen deposition and pyroptosis levels in aortic root sections were evaluated. Additionally, further treatment of atherosclerotic mice with macrophage membrane‐encapsulated GI‐Y2 was conducted to enhance the targeting ability of GI‐Y2 to atherosclerotic plaques. Results In this study, we confirmed GI‐Y2 as a novel inhibitor of GSDMD via structure‐based virtual screening and pharmacological validation. Mechanistically, GI‐Y2 directly interacts with the Arg10 residue of GSDMD and reduces the membrane binding of GSDMD‐N. Functionally, we revealed that GI‐Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD. Similarly, GI‐Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis. Furthermore, we constructed macrophage membrane‐coated GI‐Y2 nanoparticles to enhance the targeting of GI‐Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo. Conclusion This work demonstrated that GI‐Y2 can potentially alleviate CVDs by targeting GSDMD and provided a new compound for the study of GSDMD‐mediated pyroptosis. Key points We preliminarily confirmed GI‐Y2 as a novel inhibitor of GSDMD via structure‐based virtual screening and pharmacological validation. GI‐Y2 directly interacts with GSDMD and reduces the membrane binding of GSDMD‐N via the Arg10 residue. GI‐Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD and GI‐Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis. We constructed macrophage membrane‐coated GI‐Y2 nanoparticles to enhance the targeting of GI‐Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo.https://doi.org/10.1002/ctm2.70263atherosclerosisgasdermin Dmacrophagepyroptosis |
| spellingShingle | Xiaoxi Fan Zhenfeng Cheng Ruiyin Shao Keke Ye Xudong Chen Xueli Cai Shanshan Dai Zhixuan Tang Si Shi Wenyuan Zheng Weijian Huang Jibo Han Bozhi Ye The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis Clinical and Translational Medicine atherosclerosis gasdermin D macrophage pyroptosis |
| title | The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis |
| title_full | The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis |
| title_fullStr | The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis |
| title_full_unstemmed | The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis |
| title_short | The novel GSDMD inhibitor GI‐Y2 exerts antipyroptotic effects to reduce atherosclerosis |
| title_sort | novel gsdmd inhibitor gi y2 exerts antipyroptotic effects to reduce atherosclerosis |
| topic | atherosclerosis gasdermin D macrophage pyroptosis |
| url | https://doi.org/10.1002/ctm2.70263 |
| work_keys_str_mv | AT xiaoxifan thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT zhenfengcheng thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT ruiyinshao thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT kekeye thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT xudongchen thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT xuelicai thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT shanshandai thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT zhixuantang thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT sishi thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT wenyuanzheng thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT weijianhuang thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT jibohan thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT bozhiye thenovelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT xiaoxifan novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT zhenfengcheng novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT ruiyinshao novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT kekeye novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT xudongchen novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT xuelicai novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT shanshandai novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT zhixuantang novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT sishi novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT wenyuanzheng novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT weijianhuang novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT jibohan novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis AT bozhiye novelgsdmdinhibitorgiy2exertsantipyroptoticeffectstoreduceatherosclerosis |