{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:59:03Z","timestamp":1785560343027,"version":"3.56.0"},"reference-count":94,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81704055"],"award-info":[{"award-number":["81704055"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81704055"],"award-info":[{"award-number":["81704055"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>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\u2013endogenous synergy: Move from chronic exogenous supplementation to restoring the patient\u2019s 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.<\/jats:p>","DOI":"10.3390\/cimb48080781","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:00Z","timestamp":1785428100000},"page":"781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Paradigm Shift of H2S Donors in Pulmonary Arterial Hypertension Toward Precision Delivery, Endogenous Activation, and Systemic Sensitization"],"prefix":"10.3390","volume":"48","author":[{"given":"Shuang","family":"Gao","sequence":"first","affiliation":[{"name":"Graduate School, Heilongjiang University of Chinese Medicine, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8445-0120","authenticated-orcid":false,"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingli","family":"Shen","sequence":"additional","affiliation":[{"name":"Graduate School, Heilongjiang University of Chinese Medicine, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6426-4155","authenticated-orcid":false,"given":"Jieru","family":"Han","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103493","DOI":"10.1016\/j.redox.2025.103493","article-title":"Endogenous Hydrogen Sulfide Persulfidates Endothelin Type A Receptor to Inhibit Pulmonary Arterial Smooth Muscle Cell Proliferation","volume":"80","author":"Zhang","year":"2025","journal-title":"Redox Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41569-022-00741-6","article-title":"Sulfide Regulation of Cardiovascular Function in Health and Disease","volume":"20","author":"Kolluru","year":"2023","journal-title":"Nat. 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