A ROS-Responsive Dual-Functional H2S Donor for Synergistic Cardioprotection

The therapeutic utility of H2S donors in myocardial ischemia/reperfusion injury (MIRI) is hampered by the lack of spatiotemporally controlled release at the site of injury and the poor molecular economy of donor scaffolds. Herein, we designed ROS-responsive dual-functional H2S donors by conjugating a cardioprotective β-carboline with an H2O2-cleavable arylboronate H2S donor. Lead donor 7j undergoes H2O2-triggered cascade hydrolysis to corelease H2S and active β-carboline 5j. In H9c2 cardiomyoblasts, 7j concentration-dependently mitigated H2O2-induced oxidative stress, effectively suppressed apoptotic cell death, preserved mitochondrial membrane potential, and enhanced SOD/GSH-Px activities. 7j also protected HUVECs from oxidative damage, promoted migration, and restored VEGFA expression with Bax/Bcl-2 modulation. In a rat MIRI model, 7j (50 mg/kg) significantly reduced myocardial infarct size from 46.67% to 15.30%. This work establishes a synergistic molecular strategy that leverages the pathological ROS microenvironment to achieve targeted codelivery of H2S and a bioactive β-carboline, thereby offering a promising therapeutic approach for MIRI.