SLC22A4 alleviates early brain injury after subarachnoid hemorrhage with partial involvement of MCL1.

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease that causes severe early brain injury (EBI), in which neuronal apoptosis and oxidative stress are major contributors to neurological dysfunction. However, the molecular mechanisms underlying EBI remain incompletely understood. Transcriptomic analyses of the GSE73378 and GSE36791 datasets identified solute carrier family 22 member 4 (SLC22A4) as a SAH-associated gene. Public single-cell RNA sequencing data further revealed that SLC22A4 was predominantly enriched in astrocytes following SAH. In a mouse SAH model, neuronal loss, apoptosis, and reactive oxygen species (ROS) production were significantly increased and accompanied by elevated SLC22A4 expression. AAV-mediated SLC22A4 overexpression alleviated neuronal injury, reduced apoptosis and oxidative stress, and restored the expression of apoptosis- and stress-related proteins in vivo. Mechanistically, co-expression and enrichment analyses identified myeloid cell leukemia-1 (MCL1) as a candidate gene associated with SLC22A4. Their positive correlation was validated in independent transcriptomic cohorts and experimental models. In OxyHb-treated astrocytes, SLC22A4 overexpression increased MCL1 expression and attenuated apoptosis- and oxidative stress-related responses, whereas pharmacological inhibition of MCL1 with S63845 partially reversed these protective effects. Collectively, these findings suggest that SLC22A4 alleviates EBI after SAH, partly through MCL1-associated suppression of apoptosis and oxidative stress.