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<p>Thrombotic disorders remain a global health burden, necessitating novel antiplatelet agents with improved safety and efficacy. This study investigates the molecular mechanisms of two lignans, 6'-Hydroxyjusticidin B (6'-HJB) and Neojusticin A (Neo-A), isolated from <i>Justicia procumbens</i> L., through an innovative target-driven strategy integrating LC/MS, proteomics, network pharmacology, and biophysical validation. For the first time, integrin β<sub>3</sub> (ITGB3) was identified as their direct molecular target, with microscale thermophoresis (MST) confirming high-affinity binding, the dissociation constant (Kd) = 0.0642 ± 0.005&#xa0;μM for 6'-HJB; 0.0097 ± 0.001&#xa0;μM for Neo-A. This study not only elucidates the structural basis of their activity-C-6 hydroxylation in 6'-HJB enhances ITGB3 specificity, whereas Neo-A’s fused furan ring optimizes COX-1 interaction, but also establishes a paradigm shift from phenotypic screening to target-validated natural product research. The findings position 6'-HJB and Neo-A as promising candidates for the development of safer, ITGB3-mediated antithrombotic therapies, with future efforts directed toward structural optimization and preclinical validation.</p> Graphical Abstract <p></p>

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Targeting Integrin β3: novel antiplatelet lignans 6’-Hydroxyjusticidin B and Neojusticin A from Justicia procumbens unveiled via multi-omics and biophysical validation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月3日

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  • Meixian Xiang,
  • Songtao Wu,
  • Hanxiang Mei,
  • Xiang Zheng,
  • Cong Wang

摘要

Thrombotic disorders remain a global health burden, necessitating novel antiplatelet agents with improved safety and efficacy. This study investigates the molecular mechanisms of two lignans, 6'-Hydroxyjusticidin B (6'-HJB) and Neojusticin A (Neo-A), isolated from Justicia procumbens L., through an innovative target-driven strategy integrating LC/MS, proteomics, network pharmacology, and biophysical validation. For the first time, integrin β3 (ITGB3) was identified as their direct molecular target, with microscale thermophoresis (MST) confirming high-affinity binding, the dissociation constant (Kd) = 0.0642 ± 0.005 μM for 6'-HJB; 0.0097 ± 0.001 μM for Neo-A. This study not only elucidates the structural basis of their activity-C-6 hydroxylation in 6'-HJB enhances ITGB3 specificity, whereas Neo-A’s fused furan ring optimizes COX-1 interaction, but also establishes a paradigm shift from phenotypic screening to target-validated natural product research. The findings position 6'-HJB and Neo-A as promising candidates for the development of safer, ITGB3-mediated antithrombotic therapies, with future efforts directed toward structural optimization and preclinical validation.

Graphical Abstract