Macrophage GLUD1 is Essential for Redox Balance and Immune Homeostasis in Cardiac Injury

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.