Intracellular Crosstalk of the Gasotransmitter Trio (NO, CO, H2S) in Cardiovascular Health and Disease: From Molecular Signaling to Precision Gas Medicine.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) were once regarded solely as toxic environmental gases. However, accumulating evidence over the past several decades has established them as the three principal endogenous gasotransmitters that regulate a wide spectrum of physiological and pathological processes. Unlike conventional signaling molecules, gasotransmitters diffuse freely across biological membranes and exert potent biological effects through receptor-independent mechanisms, including redox-sensitive post-translational modifications and modulation of heme-containing proteins. Although the individual functions of NO, CO, and H2S have been extensively reviewed, emerging studies indicate that these gaseous mediators rarely operate in isolation. Instead, they form a highly integrated signaling network characterized by direct chemical interactions, reciprocal enzymatic regulation, and convergence upon common downstream pathways. In this mini-review, we propose the concept of a "Gasotransmitter Trio Network," emphasizing the molecular crosstalk among NO, CO, and H2S as a fundamental determinant of cellular homeostasis. We first summarize the biosynthetic pathways and major signaling mechanisms of the gasotransmitter trio, including S-nitrosylation, persulfidation, and heme-dependent regulation. We then discuss recent advances revealing how interactions among these gases generate novel bioactive intermediates and coordinate redox signaling. Particular attention is given to the emerging roles of gasotransmitters in regulating ferroptosis, autophagy, and mitophagy by modulating iron metabolism, lipid peroxidation, mitochondrial quality control, and antioxidant defense systems. These findings support a unified framework in which gasotransmitters function as master regulators of cellular fate under conditions of physiological and pathological stress. Finally, we highlight recent progress in stimuli-responsive donors, CO-releasing molecules (CORMs), NO-releasing materials (NORMs), H2S donors, and advanced nanoplatforms that enable spatiotemporally controlled gas delivery. We propose that future therapeutic strategies will increasingly rely on programmable multi-gas systems that recapitulate endogenous gasotransmitter networks. Collectively, this review provides a systems-level perspective on gasotransmitter biology and outlines emerging opportunities for the development of precision gas medicine in cardiovascular, neurodegenerative, inflammatory, metabolic, and malignant diseases.