Acoustic hydrogen delivery to treat PANoptosis induced by myocardial ischemia/reperfusion injury in rats.

Abstract

A lipid microbubble system loaded with molecular hydrogen (H₂-MBs, diameter 0.92 ± 0.03 µm, concentration ~1.14 × 10⁹ bubbles/mL) was engineered to enable ultrasound-targeted microbubble destruction (UTMD)-mediated spatiotemporal H₂ release. In a rat myocardial ischemia/reperfusion (MIR) model, intravenous administration of H₂-MBs combined with UTMD improved cardiac ejection fraction and fractional shortening, reduced infarct area, and lessened histological damage. The H₂-MBs also supported real-time contrast-enhanced ultrasound imaging. Mechanistic investigation demonstrated that locally released H₂ suppressed H₂O₂-driven PANoptosis by simultaneously downregulating pyroptosis markers (cleaved caspase-1, GSDMD), apoptosis markers (cleaved caspase-3/8, Bax/Bcl-2 ratio), and necroptosis mediators (p-RIPK1, p-RIPK3, p-MLKL). This image-guided gas delivery platform offers a strategy for coordinated modulation of programmed inflammatory cell death in MIR injury.

Mechanism

Ultrasound-triggered local H₂ release suppresses H₂O₂-induced PANoptosis by concurrently downregulating pyroptosis effectors (cleaved caspase-1, GSDMD), apoptosis regulators (cleaved caspase-3/8, Bax/Bcl-2 ratio), and necroptosis mediators (p-RIPK1, p-RIPK3, p-MLKL), thereby reducing programmed inflammatory cell death in ischemia-reperfused myocardium.