Hydrogen sulfide in ocular physiology and pathology: molecular Mechanisms, therapeutic Paradoxes, and delivery...

Hydrogen sulfide (H₂S), once known as a toxic gas, is now acknowledged as a fundamental gasotransmitter essential for ocular homeostasis. This review critically examines the paradoxical role of H₂S in the eye, how it acts as both a vital signaling molecule and a potential pathological contributor depending on concentration, cellular context, and disease stage. We explore the compartmentalized synthesis of H₂S via three principal enzymatic pathways, viz., cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and the 3-mercaptopyruvate sulfurtransferase/cysteine aminotransferase (3MST/CAT) system. Also, it's nuanced signaling through protein persulfidation, ion channel modulation (KATP, Ca²⁺), and transcriptional regulation (Nrf2/ARE, NF-κB, cAMP/cGMP). Dysregulation of H₂S dynamics is implicated in major ocular diseases, including glaucoma, diabetic retinopathy, and retinal degeneration, where it can paradoxically preserve or impair function. 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.