Targeting the ROCK/MLC/NMMHC IIA-actin signaling pathway presents a promising strategy for treating ischemic stroke and BBB-related diseases, including cerebral hemorrhage, Parkinson’s disease, and Alzheimer’s disease, etc. However, it remains unclear whether endothelial NMMHC IIA knockdown in other tissues exacerbates or mitigates brain I/R injury, warranting further investigation through multi-organ transcriptomics, parabiosis experiments, and tissue-specific knockout models to elucidate potential multi-organ endothelial crosstalk. This evidence concerns the gene MLC1 and ischemic stroke.