Hydrogen Sulfide: A Multitarget Therapeutic for Neuroinflammation in Neurodegenerative Diseases

Neurodegenerative diseases (NDDs) are characterized by the progressive degeneration of specific neuronal populations, remain incurable, and impose an escalating global health burden due to aging populations. While therapeutic options had expanded in recent years, their overall efficacy remained limited. Neuroinflammation emerged as a central factor in the pathogenesis of NDDs. Hydrogen sulfide (H₂S), an endogenous gasotransmitter known for its potent anti-inflammatory properties, gained attention as a potential therapeutic agent. This review provided a comprehensive overview of the role of neuroinflammation in NDDs, elucidated the molecular mechanisms through which H₂S exerted its anti-inflammatory effects, and discussed recent advancements and potential clinical applications. Special emphasis was placed on the modulation of glial activity, disruption of the blood-brain barrier, regulation of the gut-brain axis, and the interplay between mitochondria and inflammasomes. Furthermore, the review integrated preclinical data on dose-exposure-response relationships to define the therapeutic window of various H₂S donors. It also explored the potential of spatial multiomics and microbiota-targeted approaches to facilitate more precise H₂S-based interventions. These insights provide important scientific merit for elucidating the mechanisms of NDDs and hold urgent practical relevance for developing novel therapeutics to mitigate disease progression.