Gch1, which codes for GTP cyclohydrolase 1, is a gene with significant biological importance. It regulates the formation of Tetrahydrobiopterin (BH4), a crucial cofactor for the synthesis of essential neurotransmitters like dopamine, serotonin, and nitric oxide synthases. The BH4 synthesis pathway in which Gch1 is involved has a wide-ranging impact on various biological processes, including blood pressure regulation, vasodilatory functions, and oxidative stress [1].

Gch1 deficiency is associated with multiple neuropsychiatric diseases. In humans, certain single-nucleotide polymorphisms of Gch1 are responsible for pain in sickle cell disease, and its deficiency can lead to dopa-responsive dystonia, hyperalaninemia, Parkinson's disease, and depression [1]. In hph-1 mice (a genetic mouse model of DOPA-responsive dystonia with Gch1 mutations), reduced pain sensitivity was observed following peripheral inflammation or capsaicin sensitization, suggesting that Gch1 variants can regulate pain sensitivity, especially after pain sensitization [4]. In amyotrophic lateral sclerosis (ALS), lipid peroxidation of ferroptosis in hSOD1G93A cells and mice was related to inactivation of Gch1. SPY1, a "cyclin-like" protein, was identified as a novel ferroptosis suppressor via alleviating lipid peroxidation produced by dysregulated Gch1/BH4 axis [3]. In glioblastoma, circLRFN5 binds to PRRX2 protein and promotes its degradation, which in turn transcriptionally upregulates Gch1 expression, and Gch1 is a ferroptosis suppressor via generating the antioxidant BH4 [2].

In conclusion, Gch1 is essential for regulating neurotransmitter synthesis and antioxidant-related processes. Model-based research, especially using mouse models with Gch1 mutations, has revealed its role in multiple disease areas, such as neurodegenerative diseases, pain-related conditions, and cancer-associated ferroptosis. Understanding Gch1's functions provides potential therapeutic targets for treating these diseases.