Hydrogen sulfide modulates the miR-27a/SLC7A11 axis to inhibit ferroptosis and reduce neuronal damage in ischemic stroke

Background Ischemic stroke (IS) is a major global cause of mortality and long-term disability, and effective therapies are urgently needed. Hydrogen sulfide (H 2 S) has shown neuroprotective effects in various neurological disorders, but its mechanisms in IS remain unclear. This study aims to explore the role and mechanism of H 2 S in IS treatment. Methods IS models were established in vivo using middle-cerebral-artery occlusion (MCAO) in rats and in vitro using oxygen-glucose deprivation/reoxygenation (OGD/R) in PC12 cells. These models were treated with H 2 S donors NaHS or GYY4137. Pathological features were evaluated using TTC, FJC, H&E, and Nissl staining. Cell viability was assessed with live/dead staining and CCK-8 assay. RNA sequencing identified gene expression changes after H 2 S treatment under OGD/R conditions. Ferroptosis-related markers, lipid peroxidation (GSH, SOD, MDA), ROS levels, and the expression of SLC7A11 and GPX4 were measured by flow cytometry, Western blot, and immunofluorescence. MiR-27a levels were quantified by qRT-PCR. Results NaHS administration in MCAO rats reduced infarct volume, increased Nissl body density, and decreased degenerating neurons. GYY4137 exhibited similar neuroprotective effects in vitro. RNA sequencing revealed that GYY4137 reversed ferroptosis-related gene changes, including SLC7A11. H 2 S supplementation inhibited neuronal ferroptosis, shown by increased SLC7A11 and GPX4 expression, elevated GSH and SOD levels, and reduced MDA content. Additionally, MCAO or OGD/R induced miR-27a expression, which negatively regulated SLC7A11. H 2 S reversed this induction, and miR-27a overexpression partially blocked the anti-ferroptotic effect of H 2 S. Conclusion H 2 S alleviated IS-induced brain injury by suppressing ferroptosis, partially through miR-27a-dependent regulation of SLC7A11. These findings suggest H 2 S as a promising therapeutic agent for IS, warranting further clinical exploration.