Discovery of A ROS-Responsive Dual-Activity Hydrogen Sulfide Donor against Myocardial Ischemia Reperfusion Injury

Myocardial ischemia-reperfusion injury (MIRI) is closely associated with excessive reactive oxygen species (ROS)-mediated oxidative stress, leading to severe cardiomyocyte and endothelial damage. Hydrogen sulfide (H₂S) functions as a key cardioprotective gasotransmitter, yet the clinical translation of H₂S donors has been limited by poor selectivity and low structural efficiency. To extend the bioactivity and structural utility of H₂S donors, a series of dual-functional ROS-responsive H₂S donors were designed by conjugating a cytoprotective β-carboline fragment with an H₂O₂-cleavable arylboronate ester-based H₂S-donating trigger. The synthesized compounds (6a-6n) showed negligible cytotoxicity in H9c2 cardiomyoblasts and HUVECs. Among them, H₂S donor 6m exhibited the most potent protective effect against H₂O₂-induced injury, restoring H9c2 cell viability to 84.75% and significantly improving HUVEC survival. Mechanistic studies confirmed that 6m undergoes H₂O₂-triggered cascade hydrolysis, resulting in the sustained co-release of H₂S and the active β-carboline fragment (4m). In vitro mechanistic studies revealed that 6m attenuated cardiomyocyte apoptosis, enhanced the activities of endogenous antioxidant enzymes (SOD and GPx), and maintained mitochondrial membrane potential (ΔΨm). In a rat model of MIRI, 6m augmented myocardial antioxidant capacity, dose-dependently improved cardiac function, and reduced infarct size. These findings suggest that the dual-functional ROS-responsive H₂S donor 6m exerts synergistic cardioprotective effects through ROS scavenging and H₂S release, providing a promising therapeutic strategy for MIRI.