ORIGINAL RESEARCH article
Front. Nutr.
Sec. Nutrition and Metabolism
Volume 12 - 2025 | doi: 10.3389/fnut.2025.1647017
Taohong Siwu Decoction alleviates high salt-induced calcium overload and ferroptosis in vascular endothelial cells in hypertension by regulating ATF4
Provisionally accepted
- 1Jinan University, Guangzhou, China
- 2The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR China
- 3Xiamen University, Xiamen, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: Taohong Siwu Decoction (THSWD), a traditional Chinese medicine formula, is increasingly applied in clinical practice for hypertension management. Our previous research demonstrated that THSWD alleviates high-salt-induced hypertension in mice. This study aims to further elucidate the underlying mechanisms of THSWD in treating hypertension. Methods: The chemical composition of THSWD was identified using UPLC-Q/TOF-MS in earlier research. In this study, we performed both in vivo and in vitro experiments. ATF4+/−mice (KO) and C57BL/6 mice (WT) were fed a high-salt diet with or without THSWD treatment. Human aortic endothelial cells (HAECs) were cultured in high-NaCl conditions, with or without ATF4 inhibition. Blood pressure, vascular injury, calcium overload, and ferroptosis were measured to evaluate the protective effects of THSWD. Results: In vivo, a high-salt diet caused hypertension, vascular wall thickening, vascular injury, calcium overload, and ferroptosis, all of which were significantly alleviated by THSWD and the calcium-channel blocker nifedipine (NI). THSWD also reduced the high-salt-induced overexpression of ATF4. Similar effects were observed in vitro, where THSWD, the ferroptosis inhibitor ferrostatin-1 (Fer-1), the intracellular calcium chelator BAPTA-AM, and NI improved calcium overload and ferroptosis caused by high-NaCl. This was accompanied by reduced expression of CaMK4, CACNA1C, IP3R, RyR2, GPX4, ACSL4, and LPCAT3. Furthermore, compared to ATF4+/ −mice on a high-salt diet, those treated with THSWD showed greater reductions in blood pressure, improved vascular endothelial function, and better suppression of calcium overload and ferroptosis. Inhibition of ATF4 or co-treatment with siATF4 and THSWD in vitro also restored abnormal biomarker levels (iron, calcium, 12-HETE, 15-HETE, GSH, GSH/GSSG, MDA, and LPO) and normalized calcium overload-and ferroptosis-related markers. Conclusion: THSWD effectively lowers blood pressure and protects against vascular damage in high-salt-induced hypertension. Its protective effects are achieved by inhibiting calcium overload and ferroptosis through the regulation of ATF4.
Keywords: Taohong Siwu decoction, Hypertension, vascular endothelial injury, ATF4, calcium overload, ferroptosis
Received: 14 Jun 2025; Accepted: 26 Aug 2025.
Copyright: © 2025 Lam, Xu, Xie, Liang, Xie, Poon, Xiao and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lai Kwan Lam, Jinan University, Guangzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.