ase polyamines concentration in neuroblastomas, attenuating tumor HD1 Accession development [88,89]. The shift in arginine metabolism major to ALK6 site higher levels of polyamines will lower NO synthesis affecting NOS function [90]. Thus, although SR and GTPCH1 are on the exact same metabolic pathway, their contributions to breast cancer progression may not be the identical. In glioblastoma (GBM), in silico analyses showed that enhanced GCH1 expression was correlated with larger glioma grade, recurrence, and worse survival. Moreover, GCH1 overexpression and BH4 levels elevation in GBM cells increase proliferation and decrease survival in an intracranial GBM-mouse model, that is correlated with brain tumor-initiating cells maintenance and ROS suppression [56]. GBM development is related with high ROS levels; having said that, exceeded production can induce cell death [91,92]. On the other hand, improved NOS expression and NO is correlated with glioma cell proliferation [41,56,93]. Thus, GTPCH1/BH4/NO signaling activation in GBM cells might represent a chemoresistance mechanism, preventing cell death as in melanocyte and keratinocyte cells submitted to radiation-induced ROS [51]. Improved expression of iNOS and eNOS have been associated with esophageal squamous cell carcinoma (ESCC). Nevertheless, neither the regulation of NOS by BH4 nor the mechanism of contribution towards the pathogenesis of ESCC have not been investigated. AU-rich element RNA-binding element 1 (AUF1) is a family of proteins involved in the post-transcriptional regulation method of mRNA and has been related as a promoter or inhibitor of cancer progression [57,946]. Gao and colleagues identified that AUF1 expression is higher in ESCC when in comparison to typical or tumor-adjacent tissues. Interestingly, the AUF1 silencing decreased GCH1 expression and NO quantity, which in turn decreased cell growth and elevated apoptosis in squamous carcinoma Eca-109 cells [57]. Though not explored by the authors, the information indicate that AUF1 downregulation causes NOS uncoupling through GTPCH1 regulation in ESCC cells. Since ESCC growth suppression was triggered by endoplasmic reticulum pressure activation and improved ROS levels [97,98], NOS uncoupling may be related with oxidative stress-induced cell death. On the other hand, to confirm this hypothesis BH4, BH4/BH2, and O2 analyses are expected. Within a really elegant approach, Soula et al. showed that BH4 abrogates lipid peroxidationinduced ferroptosis caused by glutathione peroxidase 4 (GPX4) inhibition [58]. Using metabolism-focused CRISPR-Cas9 genetic screens it was shown that decreased expression of enzymes from the de novo BH4 synthesis pathway is related with cell death triggered by RSL3, a GPX4 inhibitor, in diverse cancer cell lines. Exogenous BH4 supplementation increased proliferation and restored the resistance of T- and B-cell acute lymphoblastic leukemia and lymphomas to GPX4 inhibitors, indicating BH4 synthesis as a new target therapy in those tumors. The authors showed that ferroptosis impairment was caused by the capability of BH4 to act as a radical-trapping antioxidant in lipid membranes, avoiding lipid peroxidation in accordance with another study employing fibroblasts [43]. It was also suggested that the protective part of BH4 was by an eNOS-independent mechanism. On the other hand, it was assumed that NO formation by NOS promotes the oxidation of BH4 to BH2, decreasing BH4 bioavailability, which in turn triggers NOS uncoupling and O2 generation. BH4 is not consumed within the reaction catalyzed by N