Tanshinone I alleviates post-ischemic myocardial injury by targeting TGFBR1 and modulating the TGF-β signaling pathway

Liyuan Ke; Ziyao Zheng; Shumin Ye; Chenhui Zhong; Qingyun Lin; Yan Hu; Peiying Shi; Lei Wen; Hong Yao

doi:10.1016/j.phymed.2025.156994

Tanshinone I alleviates post-ischemic myocardial injury by targeting TGFBR1 and modulating the TGF-β signaling pathway

Phytomedicine. 2025 Jun 16:145:156994. doi: 10.1016/j.phymed.2025.156994. Online ahead of print.

Authors

Liyuan Ke¹, Ziyao Zheng¹, Shumin Ye¹, Chenhui Zhong¹, Qingyun Lin¹, Yan Hu², Peiying Shi³, Lei Wen⁴, Hong Yao⁵

Affiliations

¹ Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
² Public Technology Service Center, Fujian Medical University, Fuzhou 350122, China.
³ Department of Traditional Chinese Medicine Resource and Development, College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China. Electronic address: peiyshi@126.com.
⁴ The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China. Electronic address: wenlei@zcmu.edu.cn.
⁵ Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, 350122, China. Electronic address: hongyao@mail.fjmu.edu.cn.

PMID: 40580691
DOI: 10.1016/j.phymed.2025.156994

Abstract

Background: Tanshinone I (Tan I) is an essential active ingredient of the traditional cardiovascular medicine Salvia miltiorrhiza Bunge (S. miltiorrhiza). Although the protection of Tan I on cardiomyocyte has been reported, its anti-myocardial ischemia effects and mechanisms remain unknown.

Purpose: Systematic evaluation of the role of Tan I in reducing myocardial ischemia (MI) injury and elucidation of the underlying molecular mechanisms by which Tan I improves myocardial fibrosis and ventricular function in mouse MI models.

Methods: In vivo and in vitro MI models were constructed to substantiate the anti-MI effects of Tan I. Through target fishing, molecular docking, and network pharmacology investigation, the effect mechanisms and potential target proteins of Tan I against MI were predicted further. Tandem mass tags (TMT)-based quantitative proteomics, transforming growth factor beta receptor I (TGFBR1)-overexpressing lentiviral vectors, molecular dynamics (MD) simulations, biolayer interferometry (BLI), cellular thermal shift assay (CETSA), TGFBR1 kinase activity, and drug affinity responsive target stability (DARTS) assay were subsequently used to validate the anti-MI-effect mechanisms and targets of Tan I.

Results: Tan I can markedly increase the survival of oxidative stress cell models, improve intracellular environment, and inhibit the release of intracellular reactive oxygen species. Moreover, it can restore abnormal electrocardiograms, decrease myocardial infarction area, inhibit cardiac fibrosis, and reduce serum levels of key cardiac injury biomarkers in the MI mouse model. Mechanistically, Tan I considerably inhibited the phosphorylation modification levels of TGFBR1 and Smad2 and the aberrant expressions of Collagen I/III, α-smooth muscle actin, Bcl-2, and Bax proteins in MI mice. These findings were further verified in NIH-3T3 cells overexpressing TGFBR1 or activated by TGF-β1. MD simulations, CETSA, and DARTS showed that TGFBR1 binding to Tan I was relatively stable. In addition, BLI indicated that the equilibrium dissociation constant of Tan I binding TGFBR1 was 1.5 × 10^-6 M. Based on the kinase activity assay, Tan I restrained TGFBR1 with a half-maximal inhibitory concentration of 739.6 nM.

Conclusion: This work reveals for the first time that Tan I can reduce MI injury and fibrosis by modulating the TGF-β signaling pathway via targeting of TGFBR1.

Keywords: Myocardial fibrosis; Myocardial ischemia; TGF-β signaling pathway; TGFBR1; Tanshinone I.