Soluble Guanylate Cyclase Modulators in Glaucoma and Ocular Fibrosis: Mechanisms,Translational Evidence,and Therapeutic Challenges

Abstract

The purpose is to review the role of the nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling pathway in glaucoma, focusing on trabecular meshwork (TM) function, aqueous humor outflow, intraocular pressure (IOP), and ocular fibrosis. A structured narrative review of PubMed/MEDLINE, Embase, and Web of Science identified peer-reviewed studies published from January 2000 to March 2026 using terms including “soluble guanylate cyclase,” “sGC stimulator,” “sGC activator,” “cGMP,” “nitric oxide,” “glaucoma,” “trabecular meshwork,” “aqueous humor outflow,” and “ocular hypertension.” Experimental studies involving TM cells, Schlemm’s canal endothelial cells, ocular fibroblasts, anterior segment perfusion systems, animal models, and human clinical investigations were qualitatively reviewed. Evidence supports an important role for NO–sGC–cGMP signaling in regulating conventional aqueous humor outflow. sGC activation increases intracellular cGMP and promotes protein kinase G–mediated modulation of cytoskeletal organization and RhoA/Rho kinase signaling, reducing TM contractility and increasing outflow facility. cGMP signaling may also regulate extracellular matrix remodeling and transforming growth factor-β–associated fibrotic responses in ocular tissues. Preclinical studies demonstrate enhanced outflow facility and reduced IOP after pharmacologic pathway activation. Clinical evidence is strongest for NO-donating therapies such as latanoprostene bunod, whereas direct evidence for selective sGC stimulators and activators remains limited. The NO–sGC–cGMP pathway is a promising therapeutic target in glaucoma, particularly for trabecular outflow regulation and IOP control. Despite consistent mechanistic preclinical evidence, translational challenges remain, including drug delivery, tissue-specific pharmacodynamics, and limited clinical evaluation of direct sGC modulators. Further studies are needed to define the therapeutic role of selective sGC-targeted strategies in glaucoma management.