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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
PI3K/AKT/GSK3β regulatory axis in bone mesenchymal stem cells initiates diabetic myocardial infarction via miR-142-3p
Ning Gao, Peng-Fei Wu, Ming-Wen Wu, Yu-Meng Li, Xu Liang, Fei-Fei Wang, Xue-Jing Li, Qing-Qing Shen, Tian-Peng Zheng, Xiao-Ling Liu, Yi Sun, Liu-Xue Yang
Ning Gao, Peng-Fei Wu, Fei-Fei Wang, Xue-Jing Li, Qing-Qing Shen, Tian-Peng Zheng, Liu-Xue Yang, Department of Endocrinology, The Second Affiliated Hospital of Guiln Medical University, Guilin 541004, Guangxi Zhuang Autonomous Region, China
Ming-Wen Wu, Xu Liang, Yi Sun, Department of Toxicology, Key Laboratory of Environmental Exposommics and Entire Lifecycle Heath, Guilin Medical University, Guilin 541004, Guangxi Zhuang Autonomous Region, China
Yu-Meng Li, Occupational Disease Prevention and Control Section, Zaozhuang Center for Disease Control and Prevention, Zaozhuang 277000, Shandong Province, China
Xiao-Ling Liu, Department of Endocrinology, The First Affiliated Hospital of Guilin Medical University, Guilin 541004, Guangxi Zhuang Autonomous Region, China
Co-first authors: Ning Gao and Peng-Fei Wu.
Co-corresponding authors: Yi Sun and Liu-Xue Yang.
Author contributions: Gao N and Wu MW contributed to methodology; Li YM contributed to validation; Wang FF contributed to formal analysis; Liang X contributed to investigation; Wu PF contributed to resources; Li XJ contributed to data curation; Liu XL and Sun Y contributed to writing–original draft preparation; Shen QQ and Zheng TP contributed to writing–review and editing; Yang LX contributed to supervision, project administration, funding acquisition; All authors have read and approved the final manuscript.
Supported by Health Commission Project, No. Z2014334; and Natural Science Foundation of Guangxi Province, China, No. 2020GXNSFAA238036.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Ethics Committee of Guilin Medical University (IACUC protocol number: GLMC-IACUC-2023009).
Conflict-of-interest statement: The author declares that they have no competitive interests.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yi Sun, Department of Toxicology, Key Laboratory of Environmental Exposommics and Entire Lifecycle Heath, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin 541004, Guangxi Zhuang Autonomous Region, China.
sunyide163@163.com
Received: December 6, 2024
Revised: March 12, 2025
Accepted: April 27, 2025
Published online: September 20, 2025
Processing time: 250 Days and 3.4 Hours
BACKGROUND
We aimed to identify the key proteins of miR-142-3p that regulate ferroptosis and ultimately control the downstream effectors of cardiomyocyte growth.
AIM
To investigate the role of miR-142-3p in regulating ferroptosis and its impact on diabetes-induced myocardial infarction via the PI3K/AKT/GSK3β pathway.
METHODS
We constructed bones mesenchymal stem cells (BMCs) with low miR-142-3p expression and investigated its role using cell flow cytometry and western blotting (WB). A diabetes myocardial infarction model was established using streptozotocin and coronary artery ligation. The rats were divided into six groups (n = 15 per group): Control, sham surgery model, liraglutide intervention, BMCs intervention, and low miR-142-3p BMCs intervention. Interventions lasted for 7 days and BMCs injected for once. Blood glucose levels were monitored, and myocardial infarction improvements were assessed via electrocardiogra, general heart observation, staining techniques, and WB analysis.
RESULTS
We observed that miR-142-3p increased BMC apoptosis and affected AKT and GSK3β. The myocardial infarction drug, liraglutide, BMCs, and miR-142-3p low expression BMCs intervention showed improvement in differing degrees. The liraglutide and BMCs showed significant blood glucose reduction (0.05). BMCs increased the expression of PI3K, AKT, and GSK3, leading to an increase in the myocardial infarction intervention group, liraglutide, and BMCs intervention groups. The low miR-142-3p expression intervention with BMCs group had the lowest PI3K and AKT protein expression. Liraglutide improved ferroptosis markers (increased COX-2, decreased GPX4 and CHCHD6). Low miR-142-3p BMCs increased COX-2, GPX4, and CHCHD6. CCM3 and VEGFR2 expression increased in BMCs and low miR-142-3p groups, promoting myocardial repair, but decreased in the low miR-142-3p groups.
CONCLUSION
The preliminary results showed that the therapeutic mechanism of BMCs in diabetes myocardial infarction may involve miR-142-3p via the PI3K/AKT/GSK-3β axis, which jointly inhibits ferroptosis and programmed death.
Core Tip: This study demonstrated that using bones mesenchymal stem cells (BMCs) as an intervention can simultaneously reduce blood sugar levels and promote hypoxic myocardial recovery. However, when miR-142-3p expression in BMCs was low, there was a reduced therapeutic efficacy of BMCs and activation of PI3K/AKT/GSK-3β. The regulatory axis regulates changes in the protein expression levels of the ferroptosis-related genes GPX4/CHCHD6. These findings suggest that miR-142-3p via the PI3K/AKT/GSK-3β regulation axis that jointly inhibits ferroptosis, may be one of the therapeutic mechanisms of BMCs in diabetic myocardial infarction.
