Recent Progress in Hydrogen-mediated Neuroprotection via Modulation of Mitochondrial Quality Control Mechanisms in...

Brain injury is a leading cause of mortality and long-term disability worldwide, characterized by energy metabolism dysfunction, oxidative stress, inflammatory responses, and programmed cell death, with mitochondrial dysfunction serving as a central pathological nexus. In recent years, hydrogen, as an emerging gaseous signaling molecule, has demonstrated remarkable neuroprotective effects in various experimental models of brain injury owing to its unique biological properties, including selective antioxidant, anti-inflammatory, anti-apoptotic, and mitochondrial- protective activities. This review comprehensively summarizes the protective effects and underlying molecular mechanisms of hydrogen in ischemic stroke, traumatic brain injury, hypoxic-ischemic encephalopathy, intracerebral hemorrhage, subarachnoid hemorrhage, chronic cerebral hypoperfusion, and toxic encephalopathy. Special emphasis is placed on hydrogen's ability to modulate mitochondrial quality control networks, encompassing antioxidative membrane protection, precise regulation of mitophagy, remodeling of mitochondrial dynamics, and metabolic reprogramming, thereby improving neuronal survival and functional recovery. Moreover, this review has discussed current limitations, unresolved scientific questions, and major challenges, while proposing future directions, such as multi-omics integration, advanced structural biology investigations, innovative experimental model optimization, and systematic clinical translational research. Collectively, hydrogen holds great promise as a novel mitochondriatargeted neuroprotective strategy for brain injury, offering not only a solid theoretical foundation but also a potential personalized and precise therapeutic avenue for future clinical applications in neurological disorders.