Nature Communications (Apr 2025)

A facultative plasminogen-independent thrombolytic enzyme from Sipunculus nudus

  • Mingqing Tang,
  • Guoxing Ma,
  • Chunyan Xu,
  • Hui Yang,
  • Hongjun Lin,
  • Chao Bian,
  • Chengjia Hu,
  • Meiling Lu,
  • Lei Chen,
  • Wencai Jie,
  • Zhen Yue,
  • Jianbo Jian,
  • Yuqing Sun,
  • Hui Yan,
  • Jingjing Zhou,
  • Xianying Zhang,
  • Shengye Liao,
  • Zhaofa Li,
  • Shuangfeng Cai,
  • Yaqing Wu,
  • Kexin Yang,
  • Yanan Xiong,
  • Yonggang Zhao,
  • Zhimin Lv,
  • Xiaoming Xu,
  • Chuang Liu,
  • Pengliang Xin,
  • Lichao Ye,
  • Xiuling Cui,
  • Qiong Shi,
  • Xi Chen,
  • Ruian Xu

DOI
https://doi.org/10.1038/s41467-025-58915-y
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 19

Abstract

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Abstract 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.