GYY4137 / National University of Singapore - LARVOL DELTA

Late Breaking Abstract - Slow-Releasing Hydrogen Sulphide Donor GYY4137, Alone or in Combination with Pirfenidone, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice (ERS 2026) - "These findings extend our previous observations on i.n. GYY4137 treatment and suggests a superior option to PIR for consideration as an add-on therapy. This work has been supported by the Scientific Research Projects Coordination Unit of Hacettepe University under grant number TOA-2025-21834."

Combination therapy • Late-breaking abstract • Preclinical • Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Respiratory Diseases

Development and validation of a high-performance liquid chromatography method for quantification of the hydrogen sulfide donor GYY4137 in multiple skin layers. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "GYY4137 delivery was time- and formulation-dependent, with propylene glycol and oleic acid enhancing skin penetration compared to aqueous solutions. Overall, the proposed HPLC method with UV detection provides a reliable and accessible analytical tool for routine quantification of GYY4137 and supports the development and optimization of H₂S-based topical therapies for inflammatory skin disorders."

Journal • Dermatitis • Dermatology • Inflammation

H2S-Based Strategies for Duchenne Muscular Dystrophy (ICNMD 2026) - " Using two murine DMD models (mdx and D2.mdx), we tested H2S supplementation via fast- (NaHS) and slow-releasing (GYY4137) donors, and genetic overexpression of the H2S-producing enzyme cystathionine γ-lyase (CTH)... These results demonstrate that increasing H2S levels confers protection against DMD pathology and highlight the therapeutic potential of H2S-based strategies for slowing disease progression and developing mechanism-based interventions."

Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Inflammation • Muscular Dystrophy • CASP3 • CTH • HMOX1 • SOD2 • SPP1

Mitochondrial STING Governs Glycolytic Reprogramming in Diabetic Cardiomyopathy. (PubMed, Circ Res) - "Genetic ablation of STING or pharmacological restoration of hydrogen sulfide levels with GYY4137 effectively rescued mitochondrial dysfunction, decreased lactate overproduction, and preserved cardiac contractile performance in diabetic mice. These findings identify STING as a spatial immunometabolic modulator that bridges mitochondrial dysfunction with metabolic imbalance in diabetic cardiomyopathy. Enhancing STING S-sulfhydration or targeting its palmitoylation through hydrogen sulfide-based interventions represents a promising therapeutic strategy for the treatment of diabetic cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Inflammation • Metabolic Disorders • ENO1 • STING

Hydrogen Sulfide-Releasing Compounds Attenuate Lipopolysaccharide-Induced Inflammation in Porcine Anterior Uveal Explants, Ex Vivo. (PubMed, Res Sq) - "ICBs were exposed to sodium hydrosulfide (NaHS), GYY4137, S-allyl-cysteine (SAC), and polysulfides, diallyl disulfide (DADS), and diallyl tetrasulfide (DATTS) four hours before the end of incubation...We conclude that both fast- and slow-releasing H 2 S compounds, as well as polysulfides, were effective in reducing LPS-induced acute inflammation in porcine anterior uveal explants, ex vivo. Inhibition of endogenous H 2 S biosynthesis exacerbates LPS-induced production of an inflammatory mediator, a response that was reversed by an H 2 S-releasing compound."

Journal • Preclinical • Inflammation • Ocular Inflammation • Ophthalmology • Uveitis • IL10 • IL6 • TNFA

Photoreactivity of Ru2+ Polypyridyl Complexes Bearing the H2S-Releasing Compound GYY4137. (PubMed, Inorg Chem) - "Density functional theory (DFT) calculations were carried out to probe the influence of complex structure on the ligand ejection process. These studies provide insight into the photoreactivity of Ru2+ polypyridyl complexes bearing GYY4137, results that are of relevance more broadly for the use of these scaffolds to release anionic sulfur-containing ligands."

Journal • Oncology

Hydrogen sulfide donor GYY4137 attenuates RANKL-induced osteoclast differentiation and multi-nucleation. (PubMed, J Toxicol Sci) - "Furthermore, GYY4137 suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK1/2, and p38MAPK, compared to RANKL-treated cells. Thus, our data suggested that H2S donor GYY4137 as a novel osteoclast genesis inhibitor, significantly decreases osteoclast differentiation and multi-nucleation by inhibiting the expression of the cell-cell fusion molecules."

Journal • CTSK • MAPK8 • NFATC1 • TRAP

Hydrogen sulfide alleviates hyperoxia effects on mitochondria in human developing airway smooth muscle. (PubMed, JCI Insight) - "Human fetal ASM (fASM) were exposed to moderate hyperoxia to investigate the effects of exogenous H₂S donors (GYY4137, AP39) and stabilization of cystathionine β-synthase (CBS), an H₂S biosynthetic enzyme, on mitochondrial structure and function. Hyperoxia impaired fASM mitochondrial integrity, while H₂S donors in particular, or CBS stabilization attenuated adverse O2 effects on mitochondrial morphology, reactive oxygen species, respiration, calcium regulation, and contractility. These findings highlight the therapeutic potential of H₂S in the premature lung exposed to moderate hyperoxia."

Journal • Asthma • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases

Therapeutic Potential of GYY4137 in Reducing Oxidative Stress and Mortality in Experimental Decompression Sickness. (PubMed, Sci Rep) - No abstract available

Journal

A Protective Role of Hydrogen Sulfide Donor GYY4137 Through Activated Microglia-induced Anti-inflammatory Cytokines in the Spinal Cord of Diabetic Rats. (PubMed, Mol Neurobiol) - "The treatment also prevented the loss of astrocytes and neuronal cells in the spinal cord, indicating neuroprotective effects. In conclusion, our findings suggest that H₂S can shift microglial activity from neuroinflammation to neuroprotection, highlighting its potential as a possible candidate for novel therapeutic strategy for diabetes and its complications."

Journal • Preclinical • Diabetes • Diabetic Neuropathy • Inflammation • Metabolic Disorders • Pain • IL10 • IL12A • IL13 • STAT3 • TGFB1

Investigation of organosulfur molecules in experimental acute pancreatitis: Antioxidant and antiferroptotic actions of ATB-346. (PubMed, Biomed Pharmacother) - "Our results indicate that ATB-346 possesses anti-inflammatory and cytoprotective properties, thus making it a promising candidate in the treatment of AP."

Journal • Inflammation • Pancreatitis • GPX4

Hydrogen sulfide in ocular physiology and pathology: molecular Mechanisms, therapeutic Paradoxes, and delivery challenges. (PubMed, Mol Biol Rep) - "A central translational challenge is designing controlled-release H₂S donors (e.g., GYY4137, ACS67) that replicate physiological signaling while overcoming formidable ocular bioavailability barriers. We evaluate advanced delivery platforms, from in situ gels to nanoparticle systems, that promise targeted and sustained release. By integrating molecular mechanisms with a critical appraisal of conflicting evidence, this review establishes a conceptual framework for H₂S-based therapeutics and highlights unresolved mechanistic questions and delivery hurdles that must be addressed to realize clinical potential."

Journal • Review • Diabetic Retinopathy • Glaucoma • Ophthalmology • Retinal Disorders

Endogenous H₂S promotes HSPA8 sulfhydration to downregulate HIF1α and prevent ferroptosis in septic myocardial injury. (PubMed, Redox Rep) - "We used in vitro and in vivo sepsis models we investigated the protective to examine the effects of H₂S donors (GYY4137 and Allicin) on SIMI...This study reveals a novel H₂S-HSPA8-HIF1α-BNIP3 axis in regulating ferroptosis and myocardial injury during sepsis. Protein sulfhydration mediates the cardioprotective effects of H₂S, and Allicin emerges as a promising therapeutic agent for septic cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Infectious Disease • Inflammation • Septic Shock • HIF1A • HSPA8

Cystathionine γ-lyase-dependent S-sulfhydration of Smad3: A novel target to alleviate fibrosis in systemic sclerosis. (PubMed, Arthritis Rheumatol) - "Smad3 S-sulfhydration mediates the antifibrotic effect of CSE in SSc, highlighting it as a critical mechanism and promising therapeutic target."

Journal • Fibrosis • Immunology • Respiratory Diseases • Scleroderma • Systemic Sclerosis • SMAD3 • TGFB1

Inorganic, Synthetic, Natural, and Innovative Hybrid Hydrogen Sulfide Donors and Inhibitors of Its Biosynthesis in the Treatment of Central and Peripheral Nervous System Injuries: A Systematic Analytical Review. (PubMed, Int J Mol Sci) - "Organic donors (e.g., GYY4137, ACS67, ACS84, SPRC, ADT-OH and its derivatives, S-memantine, and MTC) provide sustained H2S release, stabilize the blood-brain barrier, and exhibit antiapoptotic activity. The analysis reveals a general pattern: all classes of H2S donors effectively modulate key pathological mechanisms, differing in their rate, duration, and specificity of action. These findings highlight the therapeutic promise of H2S-based pharmacological agents in clinical neurotraumatology, while emphasizing the need for further research to optimize delivery systems, enhance efficacy, and minimize adverse effects."

Journal • Review • Cardiovascular • CNS Disorders • Inflammation • Neuralgia • Orthopedics • Pain • Vascular Neurology

Use of a Near Infrared Probe to Assess Intracellular Hydrogen Sulfide Production. (PubMed, J Surg Res) - "This NIR-HS probe was shown to be a useful compound in the detection of H2S in cell-free and cellular environments. Further studies are needed to demonstrate its use within in vivo applications of specific ischemic and inflammatory disease models prior to clinical translation."

Journal • Inflammation

Self-activated prodrug nanocomposites reprogramming lactic acid metabolism to initiate acidosis-endoplasmic reticulum stress cascade and potentiate immunogenic cell death for enhanced liver cancer therapy. (PubMed, J Nanobiotechnology) - "This system is self-assembled from a pentavalent arsenate prodrug (AsO₄³⁻), the hydrogen sulfide (H₂S) donor GYY4137, and the lactate export inhibitor diclofenac (DCF), enabling precise responsiveness to the acidic and reductive tumor microenvironment...This is evidenced by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and T cell activation. By integrating lactate metabolism regulation, prodrug activation, and immune remodeling, this strategy provides a promising avenue for combined chemo-immunotherapy of HCC."

Journal • Hepatocellular Cancer • Liver Cancer • Metabolic Disorders • Oncology • Solid Tumor • ATF4 • HSPA5

Hydrogen Sulfide Attenuates Cisplatin-Induced Acute Kidney Injury via Dual Inhibition of Apoptosis and Pyroptosis. (PubMed, Biomedicines) - "Purpose: Cisplatin chemotherapy is complicated by acute kidney injury (cis-AKI), driven by regulated cell death pathways, including apoptosis and pyroptosis. It suppressed both the early apoptotic and delayed pyroptosis cascades without reversing CBS downregulation. GYY4137 mitigated both apoptosis and pyroptosis, offering a promising multi-targeted therapy for cis-AKI."

IO biomarker • Journal • Acute Kidney Injury • Inflammation • Nephrology • Renal Disease • BAX • BCL2 • CASP3 • GSDME • IL18 • IL1B • NLRP3

Hydrogen sulfide improves vascular endothelial function in hypertensive states through SIRT6 anti-inflammatory signaling. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Using an angiotensin II (Ang II)-induced endothelial dysfunction model, we show that treatment with the hydrogen sulfide (H₂S) donor GYY4137 significantly reverses Ang II-induced damage...Critically, SIRT6 inhibitors block the protective effects of H₂S in the endothelium. This study demonstrates that H₂S protects vascular endothelial function by activating the SIRT6 anti-inflammatory pathway."

Journal • Cardiovascular • Hypertension • Inflammation • ICAM1 • IL6 • SIRT6

pH-responsive Oral liposomal delivery of hydrogen sulfide donor GYY4137 enables colon-targeted therapy for inflammatory bowel disease. (PubMed, J Nanobiotechnology) - "These findings demonstrate that Oral H₂S lipo enables effective, site-specific delivery of H₂S to inflamed colonic tissue, offering a clinically relevant platform to overcome limitations of conventional H₂S donor therapies in IBD management."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

Expression and activity of the umami taste receptor (TAS1R1/TAS1R3) in rat corpus cavernosum. (PubMed, Eur J Pharmacol) - "Isometric force recordings for the TAS1R1/TAS1R3 agonist monosodium glutamate (MSG), the NO donor SNAP, the hydrogen sulfide (H2S) donor GYY 4137, and electrical field stimulation (EFS) and measured endogenous H2S production...These findings indicate significant neuronal and endothelial expression of TAS1R1/TAS1R3 in the CC and DPA, where MSG promotes SM relaxation. In the CC, MSG enhances nerve-mediated relaxation induced by NO and H2S and stimulates H2S production, suggesting TAS1R1/TAS1R3 as a potential therapeutic target for ED."

Journal • Preclinical • Erectile Dysfunction

The CBS/H2S axis regulates intestinal stem cell homeostasis and radiation-induced intestinal damage. (PubMed, Stem Cell Res Ther) - "Our findings suggest that the CBS/H2S axis contributes to the regulation of ISC homeostasis and represents a potential target for radiation protection, mediated through the intervention of non-epithelial cells."

Journal • Gastrointestinal Disorder

The role of H2S in isoproterenol-induced cardiac hypertrophy: A comparative study using slow releaser GYY4137 and a newly synthetized fast releaser BM-112. (PubMed, Biomed Pharmacother) - "We identified impaired autophagic flux in the presence of ISO and BM-112. However, GYY4137 treatment promoted autophagy beyond basal levels.Taken together, GYY4137, but not BM-112, successfully prevented adrenergic overstimulation-induced hypertrophy by reducing oxidative stress, mitigating mitochondrial dysfunction, and enhancing autophagic flux."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders

Effect of Slow Release Hydrogen Sulfide Donor GYY4137 on Vascular Smooth Muscle and Endothelial Response in an In Vitro Ischemia-Reperfusion Model of Rat Thoracic Aorta. (PubMed, Can J Physiol Pharmacol) - "In conclusion, GYY4137 reduces oxidative stress and apoptosis markers without improving vascular dysfunction in an IR model of rat thoracic aorta. This disparity underscores the complex pathophysiology of vascular IR injury, where cellular-level protection does not readily translate to functional recovery."

Journal • Preclinical • Cardiovascular • Reperfusion Injury • CASP3

Hydrogen sulfide in placental development and pregnancy disorders: mechanisms, therapeutic potential, and translational challenges. (PubMed, Reprod Biol Endocrinol) - "Additionally, exogenous H₂S donors (e.g., GYY4137 and NaHS) have demonstrated therapeutic potential in experimental models, effectively reversing PE-like pathologies, improving placental perfusion, and restoring trophoblast function...As research continues to reveal H₂S-mediated mechanisms in placental function and pregnancy disorders, optimizing the pharmacological application and clinical translation of H₂S donors and combination therapies will be a key research focus. Advancing H₂S metabolic regulation, signaling pathways, and targeted delivery systems may drive the development of novel diagnostic tools and therapeutic strategies for pregnancy complications."

Journal • Review • Gynecology • NOS3