Citation: Wenjuan Liu, Yixu Wang, Sihan Xu, Jiawei Li, Mengting Song, Qinghe Du, Zhenzhen Wang, Qianqian Wang, Min Jiang, Gang Bai. o-Phenanthrenequinone-mediated guanidinium nucleophilic attack of tanshinone IIA to Arg145 on Annexin A2 inhibits endothelial-monocyte adhesion and contributes to relieve atherosclerosis[J]. Chinese Chemical Letters, ;2026, 37(12): 112320. doi: 10.1016/j.cclet.2025.112320 shu

o-Phenanthrenequinone-mediated guanidinium nucleophilic attack of tanshinone IIA to Arg145 on Annexin A2 inhibits endothelial-monocyte adhesion and contributes to relieve atherosclerosis

State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China

minjiang@nankai.edu.cn

gangbai@nankai.edu.cn

Received Date: 28 September 2025
Revised Date: 23 December 2025
Accepted Date: 23 December 2025
Available Online: 24 December 2025

Figures(5)

Natural products have long served as invaluable resources for drug discovery, providing unique scaffolds to investigate disease-related targets. Here, we report a novel mechanism by which tanshinone IIA (TIIA), a bioactive constituent of Salvia miltiorrhiza Bge., exerts vascular protective effects through covalent modification of Annexin A2 (ANXA2). By employing an alkynylated TIIA probe (A-TIIA) in combination with chemical proteomics, we identified ANXA2 as a direct binding target of TIIA, wherein the 11,12-ortho-phenanthrenequinone moiety of TIIA forms an amine-quinone adduct with the guanidinium group of Arg145 in ANXA2. This interaction inhibits protein tyrosine phosphatase 1B (PTP1B)-mediated dephosphorylation of ANXA2 at Tyr24, locking the protein in an inactive conformation and disrupting the ANXA2-integrin α5-focal adhesion kinase (FAK)/intercellular adhesion molecule 1 (ICAM-1) signaling axis. This study not only uncovers a previously unknown mechanism underlying the therapeutic action of TIIA but also underscores the potential of natural product-inspired covalent modifiers in modulating protein-protein interactions. The evolutionarily conserved Arg145 residue in ANXA2 emerges as a promising target site for future drug development.
- Tanshinone IIA,
- Annexin A2,
- Nucleophilic attack,
- Vascular protective,
- Atherosclerosis
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