Therapeutic gases and the Nrf2/Keap1 pathway: direct thiol modification vs. indirect modulation

The nuclear factor erythroid 2-related factor 2/Kelch-like Ech-associated protein 1 (Nrf2/Keap1) pathway is a central homeostatic module that integrates oxidant, electrophilic, inflammatory, and metabolic signals into adaptive transcriptional programs. In parallel, nitric oxide (NO), hydrogen sulfide (H2S), and molecular hydrogen (H2) have emerged as therapeutically relevant gaseous mediators with distinct chemical identities, tissue distribution profiles, and pharmacological constraints. This review re-examines these gases through a single organizing question: how can highly dissimilar small molecules converge on the same redox-defense hub? We compare the direct cysteine chemistry of NO and H2S with the mainly indirect actions proposed for H2, and we use the Nrf2/Keap1 axis as the mechanistic backbone for that comparison. NO and H2S are best understood as redox-active signaling gases capable of covalent protein modification, whereas H2 appears to act largely by reshaping upstream oxidative events, mitochondrial electron leakage, membrane lipid oxidation products, and stress-responsive signaling states. Despite these differences, all three gases can feed into overlapping kinase pathways, mitochondrial quality-control networks, and cytoprotective gene programs. A second goal of this review is to move beyond single-gas narratives. We discuss the extent to which gas-gas crosstalk, especially between NO and H2S and the buffering role proposed for H2 under severe oxidative stress, may create systems-level convergence rather than simple additive antioxidant effects. We argue that the most productive conceptual model is not "one gas, one target", but a context-dependent gas signaling network centered on Nrf2/Keap1, mitochondrial adaptation, and thiol chemistry. Finally, we assess the translational implications of this framework across ischemia-reperfusion injury, neurodegeneration, metabolic disease, and aging. We highlight the practical constraints that still limit clinical implementation, including dose windows, burst release, tissue targeting, biomarker selection, and the difficulty of tracking reversible cysteine modifications in vivo. By placing NO, H2S, and H2 into one comparative redox framework, this review aims to clarify what is established, what remains inferential, and where future combination strategies may realistically emerge.