Mechanisms and therapeutic potential of hydrogen sulfide in traumatic central nervous system injuries

Traumatic central nervous system injuries encompass brain and spinal cord injuries. Recent studies have identified hydrogen sulfide (H₂S) as a potent endogenous gasotransmitter with multifaceted roles in neuroprotection and central nervous system repair. In this systematic review, we explore the mechanisms and therapeutic potential of H₂S in traumatic central nervous system injuries, emphasizing its anti-inflammatory, antioxidant, and anti-apoptotic properties. H₂S suppresses inflammation by modulating the nuclear factor-kappa B pathway, shifting microglial polarization to a reparative phenotype. Further, it mitigates oxidative stress by activating the nuclear factor erythroid 2-related factor 2 and mechanistic target of the rapamycin pathway, and inhibiting glutamate-mediated damage. Additionally, H₂S regulates cell death by inhibiting apoptosis, ferroptosis, pyroptosis, and autophagy while promoting axonal growth and microvascular integrity. Emerging H₂S delivery strategies, including slow-releasing donors such as GYY4137 and advanced hydrogel-based systems, address challenges in achieving sustained and targeted therapeutic effects. Although preclinical evidence has demonstrated the promise of H₂S-based therapies, further research is required to optimize delivery methods, investigate concentration-dependent effects, and validate clinical efficacy. This review provides a comprehensive foundation for advancing H₂S as a therapeutic agent in traumatic central nervous system injuries.