Molecular hydrogen as a novel regulator of cellular pyroptosis: mechanistic insights and therapeutic implications

Pyroptosis, a highly inflammatory programmed cell death pathway, drives pathogenesis in numerous diseases through gasdermin-mediated membrane pore formation and massive cytokine release. While conventional anti-inflammatory therapies show limited efficacy, hydrogen emerges as a novel therapeutic agent with unique pyroptosis-regulatory capabilities. This review establishes a comprehensive mechanistic framework demonstrating that hydrogen modulates pyroptosis through interconnected pathways including direct gasdermin redox modification, mitochondrial signaling integration, and inflammasome assembly disruption. Systematic analysis across diverse disease models-cardiac ischemia-reperfusion, neuroinflammation, metabolic dysfunction, and cancer-reveals hydrogen's remarkable context-dependent effects: cytoprotective in normal tissues while promoting therapeutic pyroptosis in malignant cells. Hydrogen's regulatory mechanisms exhibit striking tissue specificity and temporal complexity, with immediate antioxidant effects transitioning to sustained anti-inflammatory responses. Despite compelling preclinical evidence demonstrating efficacy in myocardial injury, neurodegeneration, and systemic inflammation, significant translational barriers remain including delivery optimization, dosimetric standardization, and biomarker development. This review critically evaluates hydrogen's transformative therapeutic potential while addressing realistic implementation challenges, providing a roadmap for advancing this innovative paradigm from bench to bedside.