Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury

Xiangyi Pu; Qiaomin Wu; Zhaoqi Yan; Siyuan Zhou; Qin Zhang; Xinai Zhang; Yongyuan Cai; Zhiming Liu; Ruxiu Liu; Xing Chang

doi:10.1016/j.phymed.2025.156982

Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury

Phytomedicine. 2025 Jun 16:145:156982. doi: 10.1016/j.phymed.2025.156982. Online ahead of print.

Authors

Affiliations

¹ China Academy of Chinese Medical Sciences Guang'anmen Hospital, Beijing 100053, China.
² China Academy of Chinese Medical Sciences Guang'anmen Hospital, Beijing 100053, China. Electronic address: liuruxiu1@163.com.
³ China Academy of Chinese Medical Sciences Guang'anmen Hospital, Beijing 100053, China. Electronic address: xingchang_tcm@outlook.com.

PMID: 40543233
DOI: 10.1016/j.phymed.2025.156982

Abstract

Background: Traditional Chinese medicine (TCM) has demonstrated significant advantages in the treatment of coronary microvascular injury, offering novel therapeutic strategies for cardiovascular diseases. Among its active compounds, Tanshinone IIA (TS) has been shown to regulate mitochondrial and endoplasmic reticulum (ER) function. However, the precise mechanisms through which TS exerts its effects, particularly via METTL3- and SIRT5-mediated unfolded protein response (UPR) pathways in microvascular endothelial cells (MECs), remain poorly understood.

Purpose: This study aims to elucidate the role of SIRT5 and METTL3 in mediating the protective effects of TS on mitochondrial and ER function in MECs, focusing on the UPR pathways.

Study design: Cardiomyocyte-specific knockout and transgenic mice were utilized to investigate the role of SIRT5 and METTL3. MECs from experimental groups were treated with TS, and various cellular functions were analyzed.

Methods: The study employed confocal microscopy, electron microscopy, JC-1 assay, MTT assay, and molecular docking techniques to assess mitochondrial and ER functions. Key markers, including mitochondrial membrane potential, protein expression (PINK1, Parkin, PERK, CHOP, and Nrf-1), and transcription levels (PGC1-α, TFAM, and ATF5), were quantified. Calcium ion levels and mitochondrial respiratory functions were also evaluated.

Results: TS treatment enhanced mitochondrial stability, restored mitochondrial membrane potential, and regulated calcium overload through METTL3- and SIRT5-mediated UPR pathways. It upregulated protective proteins (PGC1-α, TFAM, and Nrf-1) while reducing oxidative stress and ER stress markers (CHOP, PERK, and ATF5). Molecular docking confirmed a direct interaction between SIRT5 and METTL3. These changes collectively mitigated microvascular endothelial damage and normalized mitochondrial biogenesis.

Conclusion: TS exerts protective effects on MECs by stabilizing mitochondrial function, alleviating calcium overload, and modulating UPR signaling via METTL3 and SIRT5.

Keywords: Endothelial protection; METTL3; Mitochondrial function; SIRT5; Tanshinone iia; Unfolded protein response.