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Targeting GSNO Reductase: A Promising Therapeutic Path for Multiple Sclerosis

Tartin Huan^{* *}Correspondence: Tartin Huan, Department of Pulmonology, Autónoma University, Madrid, Spain, Email:

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Description

Multiple Sclerosis (MS) continues to challenge the scientific and medical community with its complexity and devastating effects. It is a disease characterized by immune-driven inflammation, demyelination, and progressive neurodegeneration in the central nervous system. While historically viewed as a T cell-dominant condition, there’s increasing recognition that B cells also play a critical role in MS pathogenesis. Despite this growing understanding, therapeutic options still lag behind in their ability to modulate the disease without broadly suppressing the immune system. Recent findings on GSNO reductase inhibitors offer new hope not only for managing symptoms but potentially transforming how we treat this debilitating disease.

At the heart of this new approach lies a molecule known as S- nitrosoglutathione (GSNO), a stable carrier of Nitric Oxide (NO) that regulates a variety of cellular processes, including immune function. GSNO levels are tightly controlled in the body by an enzyme called GSNO reductase (GSNOR). When GSNOR is overactive, GSNO levels drop, disrupting NO-based signaling and impairing immune regulation. The emerging strategy involves inhibiting GSNOR to restore GSNO balance and guide the immune system away from autoimmunity.

In a recent study, researchers expanded on prior findings that showed how GSNOR inhibition suppresses the overactive T cells specifically Th1 and Th17 subsets which are well-known drivers of MS pathology. They now demonstrate that the same therapeutic approach can also modulate B cell responses, a crucial advance given B cells’ growing recognition in MS immunopathology. Using a B cell-dependent model of Experimental Autoimmune Encephalomyelitis (EAE), a mouse version of MS, they treated animals with N6022, a GSNOR inhibitor. The results were striking.

Treatment with N6022 not only reduced clinical symptoms of EAE but also shifted the immune environment from pro- inflammatory to regulatory. The drug increased the number of regulatory B cells (Bregs) a rare subset of B cells that produce IL-10, a key anti-inflammatory cytokine and reduced the production of IL-6, a potent stimulator of pathogenic T cells. Furthermore, N6022 also promoted regulatory T cells and decreased harmful Th1 and Th17 responses. This rebalancing of immune responses in both B and T cell compartments points to a coordinated and well-regulated immune suppression, without the collateral damage of global immunosuppression.

A gentler approach: GSNOR inhibition modulates immunity without broad suppression

This dual-targeting capability is particularly exciting because it bypasses one of the biggest hurdles in MS treatment: how to suppress autoimmunity without compromising overall immune defense. Most current treatments, such as anti-CD20 monoclonal antibodies, deplete B cells entirely, leaving patients vulnerable to infections and other complications. Fingolimod and similar agents trap immune cells in lymph nodes but may impair immune surveillance. In contrast, GSNOR inhibition reshapes immune function rather than shutting it down a subtle but revolutionary difference in strategy.

Moreover, the study found that GSNOR inhibition suppressed the maturation of B cells into plasma cells, which are responsible for producing the autoantibodies that contribute to MS-related damage. By reducing this autoantibody load without eradicating all B cells, N6022 again shows a more refined approach to immune modulation.

The broader implication is this: GSNOR inhibitors could represent a new class of immunotherapies that work with the immune system rather than against it. They don’t merely block immune cells they teach them to behave. This kind of therapy has the potential not just to suppress symptoms but to encourage long-term immune tolerance, a long-sought goal in autoimmune diseases like MS.

In the era of precision medicine, one-size-fits-all immunosuppression feels increasingly outdated. If GSNOR inhibitors continue to perform as they have in preclinical studies, they could herald a new age in autoimmune disease treatment one where the immune system is no longer the enemy but a partner in healing.

Conclusion

Targeting S-nitrosoglutathione reductase presents a promising therapeutic strategy for multiple sclerosis (MS), a disease marked by neuro inflammation, demyelination, and immune dysregulation. By modulating the levels of S-nitrosoglutathione, an endogenous nitric oxide donor with anti-inflammatory and neuroprotective properties, GSNOR inhibition helps restore redox balance and protect against oxidative damage. Preclinical studies have demonstrated that GSNOR inhibitors can reduce neuroinflammation, preserve myelin integrity, and improve neurological outcomes in MS models. While clinical translation remains in its early stages, the growing body of evidence underscores the therapeutic potential of GSNOR as a novel target. Continued research into the pharmacological modulation of GSNOR activity, including safety and efficacy trials, could open new avenues for MS treatment, particularly for patients unresponsive to existing therapies.