A Paradigm Shift of H2S Donors in Pulmonary Arterial Hypertension Toward Precision Delivery, Endogenous Activation, and Systemic Sensitization

First-generation H2S donors fail in pulmonary arterial hypertension (PAH) not due to lack of efficacy, but because they release H2S indiscriminately. This review articulates a conceptual framework for advancing H2S donor therapy along three complementary directions. Donor 2.0 for precision delivery: Donors remain inert in normal tissues, but release H2S upon sensing PAH microenvironment signals [reactive oxygen species (ROS), hypoxia, esterases, matrix metalloproteinases (MMPs)], combined with lesion-selective enrichment and organelle targeting. Donor–endogenous synergy: Move from chronic exogenous supplementation to restoring the patient’s own H2S synthesis via epigenetic derepression of CSE, oxidative reactivation of CBS, and substrate support for 3-MST. Systemic sensitization: Redefine H2S donors as combination enhancers that reverse acquired insensitivity to ERAs, PDE5i, and prostacyclin analogues through protein S-sulfhydration. These three mutually reinforcing dimensions transform H2S donors from passive releasers into programmable, context-sensitive therapeutic platforms, addressing the fundamental limitations of current PAH therapies.