Immunomodulatory and anti-inflammatory potential of S-nitrosoglutathione (GSNO) in multiple sclerosis: a review of mechanisms and therapeutic perspectives

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS), characterized by sustained neuroinflammation, oxidative stress, demyelination, and progressive neurodegeneration. Although MS remains incurable, current disease-modifying therapies (DMTs) help reduce relapse frequency and delay disease progression. Recently developed injectable and infusion-based biologic DMTs offer targeted immunomodulation, but their clinical utility is limited by parenteral administration and the potential for immunogenicity. In contrast, small-molecule DMTs such as fingolimod and teriflunomide provide greater dosing convenience and flexibility; however, their broad immunosuppressive effects often lead to treatment-induced lymphopenia and increased susceptibility to infections. These limitations underscore the need for small-molecule DMTs that achieve selective immunomodulation without compromising systemic immune competence. S-nitrosoglutathione (GSNO), an endogenous nitric oxide (NO•) carrier molecule, has recently emerged as a promising candidate for immunomodulation. GSNO also mitigates oxidative stress, preserves blood-brain barrier integrity, and suppresses neuroinflammatory signaling via S-nitrosylation of key transcription factors such as Nrf2, HIF-1α, NF-κB, and STATs. The therapeutic potential of GSNO in MS is further supported by the development of reversible GSNO reductase (GSNOR) inhibitors, which elevate endogenous GSNO levels. These inhibitors have demonstrated favorable safety profiles in clinical trials for asthma and cystic fibrosis. In preclinical models of MS, GSNOR inhibitors suppress pathogenic Th1 and Th17 cells and IL-6-producing effector B cells while promoting regulatory T- and B-cell populations, thereby providing selective immunomodulation without broad immune suppression. As a result, they significantly reduce inflammation-driven demyelination. Building on this evidence, this review examines the GSNO/GSNOR axis as an emerging therapeutic target in MS, highlighting its mechanistic roles in selective immune modulation, the regulation of neuroinflammation, and the attenuation of oxidative stress. Furthermore, we discuss the translational potential of reversible GSNOR inhibitors, which have demonstrated favorable safety and tolerability in Phase I/II studies for asthma and cystic fibrosis, while emphasizing the need for future clinical evaluation of their therapeutic efficacy in MS.