MAPK3, STAT3, G6PD, and PGD are ferroptosis-associated candidate genes in aSAH, supported by human peripheral-blood, mouse cortex, single-cell, and mouse brain validation, while ganoderic acid A remains an exploratory in silico candidate requiring further functional validation.
Of 2,645 differentially expressed genes in human aSAH peripheral blood, 35 were ferroptosis-related.
MAPK3, STAT3, G6PD, and PGD were prioritized as ferroptosis-associated candidate genes and were upregulated in human aSAH peripheral blood, mouse SAH cortex, and a clinical qPCR cohort.
Single-cell RNA-seq of mouse SAH brain showed expression of the corresponding mouse genes across annotated brain cell types, especially immune and glial populations.
In mouse SAH brain tissue 1 day after SAH, protein levels of MAPK3/ERK1, STAT3, PGD, and G6PD increased, and the p-STAT3/STAT3 ratio was elevated.
Mouse SAH brain showed markers of ferroptosis-related injury: increased MDA content and decreased GPX4 activity.
Immune profiling showed increased neutrophils, mast cells, and activated dendritic cells in aSAH.
Ganoderic acid A was prioritized as a preliminary in silico drug candidate by molecular docking.
This study looked for genes linked to ferroptosis, an iron-dependent form of cell death, in aneurysmal subarachnoid hemorrhage (aSAH), a bleeding stroke with high rates of illness and death. Using public gene-expression data from human blood (43 aSAH patients, 18 controls), the researchers narrowed 2,645 changed genes to 35 ferroptosis-related ones, and then to four main candidates: MAPK3, STAT3, G6PD, and PGD. These four genes were higher in patient blood, in mouse brain cortex after SAH, and in a small blood test of 10 patients versus 10 controls. In mice with experimentally induced SAH, the matching proteins were also elevated, along with signs of ferroptosis-related damage (more lipid-damage product MDA and lower GPX4 activity). The genes were found in many brain cell types, especially immune and glial cells, and immune cell types such as neutrophils and mast cells were increased. The research suggests these genes could be useful markers or targets for understanding brain injury after aSAH. A compound called ganoderic acid A was flagged by computer docking as a possible drug candidate, but this is only a preliminary computational result. The human validation group was small, and the findings show association rather than proof of cause, so further functional studies would be needed.
Li J, Wang C, Li H, Liu Y, Cheng C, Zhao Z, et al.. (2026). Ferroptosis-associated candidate genes in aneurysmal subarachnoid hemorrhage: evidence from human peripheral blood and mouse brain.. Frontiers in neurology. https://doi.org/10.3389/fneur.2026.1823039