IL6 Regulates Glutamate/Haptoglobin-Induced Ferroptosis via the JAK2/STAT3 Axis

Ischemia-reperfusion injury severely impacts the heart and brain, and although ferroptosis is a key therapeutic target, the role of interleukin-6 in regulating ferroptosis during cardiac and cerebral I/R remains unclear. In vitro oxygen-glucose deprivation (OGD)-treated PC12 and H9C2 cells and in vivo myocardial I/R mice and MCAO rats were used to model ischemic injury. IL6 expression was silenced using siRNA or lentivirus, whereas IL-6 overexpression was achieved using an IL6 overexpression plasmid. Cells or animals were subsequently treated with glutamate (Glu), haptoglobin (HP), ferrostatin-1 (Fer-1), or colivelin, a JAK2/STAT3 pathway agonist. IL6 knockdown significantly suppressed OGD-induced ferroptosis by upregulating GPX4 and SLC7A11, thereby improving cell survival and reducing ROS and Fe²⁺ accumulation. IL6 silencing attenuated OGD-induced apoptosis, effects that were significantly abolished by Glu or HP. In myocardial I/R and MCAO models, IL6 knockdown preserved cardiac function, reduced cerebral infarction, alleviated oxidative stress, and mitigated ferroptosis, whereas Glu or HP co-treatment reversed these benefits. Mechanistically, IL6 silencing inhibited JAK2/STAT3 activation, while colivelin treatment reinstated pathway phosphorylation and ferroptosis. IL6 downregulation alleviates cardiac and cerebral I/R injuries by suppressing ferroptosis through regulation of the JAK2/STAT3 pathway.