A facultative plasminogen-independent thrombolytic enzyme from Sipunculus nudus
Current thrombolytic therapies primarily function by converting plasminogen into plasmin, a process dependent on the fibrin-activator complex. This dependence, coupled with the substantial molecular size of plasmin, constrains its effectiveness in degrading D-dimer and restricts its diffusion within thrombi. Here, we introduce a small facultative plasminogen-independent thrombolytic enzyme, snFPITE, isolated from Sipunculus nudus. Compared to traditional thrombolytic agents, snFPITE does not require plasminogen for thrombolysis, although its presence enhances lytic activity. This enzyme fully degrades cross-linked fibrin without leaving residual nondegradable D-dimer and generates a smaller fibrinolytic-active agent from plasminogen. A series of male rats and mice models further confirm that snFPITE is a safety injectable thrombolytic agent. Mechanistically, snFPITE activates plasminogen and degrades fibrin(ogen) in a multisite cleavage manner. snFPITE is inhibited by plasminogen activator inhibitor 1 and α2-antiplasmin via a competitive inhibition. We further identify 28 snFPITE candidate sequences, of which 10 are confirmed as functional genes.
Authors
- Pengliang Xin
- Shuangfeng Cai
- Mingqing Tang (ORCID: https://orcid.org/0000-0003-2501-4436)
- Xiao‐Ming Xu (ORCID: https://orcid.org/0000-0002-7229-0081)
- Chao Bian (ORCID: https://orcid.org/0000-0001-9904-721X)
- Hongjun Lin (ORCID: https://orcid.org/0000-0002-0877-8189)
- Qiong Shi (ORCID: https://orcid.org/0000-0002-6358-976X)
- Kexin Yang
- Xiuling Cui (ORCID: https://orcid.org/0000-0001-5759-766X)
- Meiling Lü (ORCID: https://orcid.org/0000-0001-8738-987X)
- Wencai Jie
- Yaqing Wu (ORCID: https://orcid.org/0000-0001-8551-6142)
- Chuang Liu (ORCID: https://orcid.org/0000-0002-5573-738X)
- Zhen Yue (ORCID: https://orcid.org/0000-0001-6993-6067)
- Shiyong Liao (ORCID: https://orcid.org/0000-0003-4222-059X)
- Zhaofa Li (ORCID: https://orcid.org/0000-0002-1838-6314)
- Zhimin Lv (ORCID: https://orcid.org/0000-0002-7313-5796)
- Jianbo Jian (ORCID: https://orcid.org/0000-0003-2187-5490)
- Hui Yang (ORCID: https://orcid.org/0000-0001-7567-3048)
- Xiang Zhang (ORCID: https://orcid.org/0000-0002-5916-1357)
- Yuqing Sun
- Ruian Xu (ORCID: https://orcid.org/0000-0002-1339-3160)
- Chen Lei (ORCID: https://orcid.org/0000-0002-9317-5576)
- Yanan Xiong
- Hui Yan (ORCID: https://orcid.org/0000-0003-1462-8520)
- Chunyan Xu (ORCID: https://orcid.org/0000-0003-4095-9569)
- Jingjing Zhou (ORCID: https://orcid.org/0009-0000-1874-9296)
- Xi Chen (ORCID: https://orcid.org/0000-0001-8295-2854)
- Guoxing Ma (ORCID: https://orcid.org/0000-0002-4840-7286)
- Lichao Ye (ORCID: https://orcid.org/0000-0001-7706-5644)
- Zhao Yong-gang
- Chengjia Hu
Institutions
- BGI Group (China) (CN)
- Huaqiao University (CN)
- Fujian Medical University (CN)
- Ministry of Education of the People's Republic of China (CN)
- Shenzhen University (CN)
- Xiamen University (CN)
- Tangshan Normal University (CN)
- Second Affiliated Hospital of Fujian Medical University (CN)
- Sanya University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Xiamen University of Technology (CN)
- Guangdong Ocean University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1038/s41467-025-58915-y
- Citations
- 2
- Primary Topic
- Protease and Inhibitor Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.87