Gastrodin: Modulating the xCT/GPX4 and ACSL4/LPCAT3 pathways to inhibit ferroptosis after ischemic stroke

Ischemic stroke ranks as the second leading cause of global mortality and disability. Although reperfusion is crucial for salvaging brain tissue, it carries the risk of secondary injuries, such as ferroptosis. Gastrodin, a neuroprotective compound found in Chinese herbal medicine, may regulate this process. However, its impact on stroke-induced ferroptosis remains unclear.

Objective: This research endeavors to probe Gastrodin's influence on post-ischemic ferroptosis, deciphering its mechanisms and assessing its therapeutic promise.

Methods: We developed rat models of middle cerebral artery occlusion/reperfusion (MCAO/R) and created oxygen-glucose deprivation/reoxygenation (OGD/R)-damaged PC12 cell models. Gastrodin was administered to assess ferroptosis using Prussian blue staining and fluorescence probes. To investigate the effects of gastrodin on the xCT/GPX4 and ACSL4/LPCAT3 pathways, we employed molecular docking, immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, we used transmission electron microscopy and JC-1 fluorescence probes to examine mitochondrial integrity and function.

Results: Our study demonstrated that gastrodin significantly reduced iron accumulation and lipid peroxidation in the brains of MCAO/R rats and OGD/R-injured PC12 cells. It suppressed reactive oxygen species (ROS) and ameliorated mitochondrial membrane potential. It potentiates the xCT/GPX4 axis while repressing the ACSL4/LPCAT3 pathway, leading to improved mitochondrial architecture and function, notably characterized by decreased mitochondrial membrane potential, reduced ROS levels, and increased formation of mitochondrial cristae. By modulating the xCT/GPX4 and ACSL4/LPCAT3 pathways, gastrodin mitigated ferroptosis in ischemic stroke, thereby preserving mitochondrial structural and functional integrity. This study provides novel mechanistic insights into gastrodin's therapeutic potential for treating ischemic stroke, highlighting the importance of traditional Chinese medicine in modern medical therapy.