Thioredoxin system: mechanisms and therapeutic potential in mental disorders

Mental disorders, including depression, schizophrenia (SCZ), autism spectrum disorders (ASD), and substance use disorders (SUD), impose a substantial global disease burden. The pathogenesis of these diseases is complex and not fully understood, which limits the therapeutic efficacy of existing interventions. Cumulative evidence indicates that redox imbalance, impaired neurogenesis, neuroinflammation, neurotransmitter dysregulation, mitochondrial dysfunction, synaptic dysfunction, and ferroptosis represent core pathological processes underlying mental disorders. The thioredoxin (Trx) system, a core machinery for intracellular redox homeostasis, comprises Trx, thioredoxin reductase (TrxR), nicotinamide adenine dinucleotide phosphate (NADPH), and thioredoxin-interacting protein (TXNIP). Multiple studies have documented the Trx system dysregulation across diverse mental disorders contributes to disease onset and progression. In this review, we summarize the structural composition and biological functions of the Trx system and discuss its possible molecular mechanisms in four major mental disorders. We also describe crosstalk between the Trx system and the glutathione (GSH) system and dissect the therapeutic prospects and translational bottlenecks of Trx-targeted pharmacological strategies. Future research directions are also outlined. Collectively, the Trx system serves as a promising candidate target for unraveling redox-dependent pathophysiological mechanisms in mental disorders. Nevertheless, multi-dimensional mechanistic and translational investigations are urgently required before Trx-based therapeutics can yield tangible clinical benefits for patients with psychiatric conditions.