Macrophage GLUD1 is Essential for Redox Balance and Immune Homeostasis in Cardiac Injury.
6 affiliations
- 1Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center For Cardiovascular Innovative Devices of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- 2School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
- 3Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center For Life and Health, Zhejiang University, Hangzhou, China.
- 4College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, China.
- 5Laboratory of Tumor Inflammation and Angiogenesis, Center For Cancer Biology, VIB, Leuven, Belgium.
- 6Laboratory of Tumor Inflammation and Angiogenesis, Center For Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
Abstract
Excessive free radical production and dysregulated immune responses contribute to myocardial ischemia-reperfusion (IR) injury. However, the mechanisms by which macrophages regulate reactive oxygen species (ROS) homeostasis and orchestrate immune responses during IR injury remain elusive. Here, we show that glutamate dehydrogenase 1 (GLUD1) expression is induced in monocytes from patients with acute myocardial infarction after interventional therapy and in cardiac-recruited macrophages from mice subjected to IR injury. GLUD1-deficient macrophages exacerbate IR injury by increasing mitochondrial ROS accumulation and amplifying pro-inflammatory responses. Mechanistically, GLUD1 deficiency leads to mitochondrial ROS accumulation due to reduced NADPH/NADP⁺ and GSH/GSSG ratios during IR injury. Elevated mitochondrial ROS inhibits PHD2 activity, stabilizing HIF-1α and enhancing NF-κB signaling, promoting the release of pro-inflammatory factors and exacerbating myocardial damage. Systemic activation of GLUD1 or adoptive transfer of monocytes pre-treated with a GLUD1 activator preserved cardiac function and mitigated IR injury. These findings highlight macrophage GLUD1 as a critical regulator of redox balance and immune homeostasis, presenting a promising therapeutic target for alleviating IR injury and preserving cardiac function.
Related
- Placental Iron Homeostasis: Navigating the Delicate Balance Between Transport and Ferroptosis
- Gui Gan Shen Mai Yin attenuates cardiac hypertrophy and dysfunction in association with mitochondrial homeostasis and the PI3K/AKT1 signaling pathway
- SIK2 antagonizes postinfarction cardiac repair by driving macrophage proinflammatory and impairing efferocytosis
- Hepatic retromer is essential for systemic cholesterol homeostasis by regulating lysosomal cholesterol handling
- Comparative analysis of the hemodynamic and metabolic effects of alternative fluid resuscitation strategies in critically ill patients with combined chest trauma and hemorrhagic shock: impact on oxygen delivery-consumption balance and coagulation homeostasis.
BibTeX
@article{jin2026macrophage,
title = {{Macrophage GLUD1 is Essential for Redox Balance and Immune Homeostasis in Cardiac Injury.}},
author = {Tingting Jin and Chaojie Lai and Qingyan Zhou and Ruilin Wang and Yiping Tong and Wentao Chen and Nikola Rabrenovic and Tingyu Zhang and Xinrong Ren and Chengchen Huang and Jiawen Chen and Ran Li and Luyang Yu and Massimiliano Mazzone and Wenbin Zhang and Guosheng Fu and Min Shang},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78416},
url = {https://europepmc.org/article/MED/42952152},
note = {CC BY},
}
RIS
TY - JOUR
TI - Macrophage GLUD1 is Essential for Redox Balance and Immune Homeostasis in Cardiac Injury.
AU - Tingting Jin
AU - Chaojie Lai
AU - Qingyan Zhou
AU - Ruilin Wang
AU - Yiping Tong
AU - Wentao Chen
AU - Nikola Rabrenovic
AU - Tingyu Zhang
AU - Xinrong Ren
AU - Chengchen Huang
AU - Jiawen Chen
AU - Ran Li
AU - Luyang Yu
AU - Massimiliano Mazzone
AU - Wenbin Zhang
AU - Guosheng Fu
AU - Min Shang
PY - 2026
DA - 2026/10/28
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78416
UR - https://europepmc.org/article/MED/42952152
AB - Excessive free radical production and dysregulated immune responses contribute to myocardial ischemia-reperfusion (IR) injury. However, the mechanisms by which macrophages regulate reactive oxygen species (ROS) homeostasis and orchestrate immune responses during IR injury remain elusive. Here, we show that glutamate dehydrogenase 1 (GLUD1) expression is induced in monocytes from patients with acute myocardial infarction after interventional therapy and in cardiac-recruited macrophages from mice subjected to IR injury. GLUD1-deficient macrophages exacerbate IR injury by increasing mitochondrial ROS accumulation and amplifying pro-inflammatory responses. Mechanistically, GLUD1 deficiency leads to mitochondrial ROS accumulation due to reduced NADPH/NADP⁺ and GSH/GSSG ratios during IR injury. Elevated mitochondrial ROS inhibits PHD2 activity, stabilizing HIF-1α and enhancing NF-κB signaling, promoting the release of pro-inflammatory factors and exacerbating myocardial damage. Systemic activation of GLUD1 or adoptive transfer of monocytes pre-treated with a GLUD1 activator preserved cardiac function and mitigated IR injury. These findings highlight macrophage GLUD1 as a critical regulator of redox balance and immune homeostasis, presenting a promising therapeutic target for alleviating IR injury and preserving cardiac function.
SN - 2198-3844
ER -