GCH1 (GTP Cyclohydrolase 1)

Moreover, overexpression of GCH1 reversed Cur-induced ferroptosis and malignant phenotype inhibition in A549 and H520 NSCLC cells. Our study suggested that Cur induced ferroptosis and suppressed malignant phenotypes in NSCLC in part through the WTAP-GCH1 axis, thereby revealing a novel mechanism for its therapeutic potential.

Coculture of the cells with macrophages revealed that the silencing of GCH1 led to decreased expression of tumor necrosis factor (TNF), a biomarker of M1 macrophages. In this study, we performed a thorough investigation of ferroptosis-related genes and identified the functional complexity of GCH1 during tumorigenesis in cervical cancer.

Our results indicate that CAFs-derived exosomes are a key source of HOXC8 in lung cancer cells. HOXC8 directly binds to the GCH1 promoter to activate its transcription, which in turn suppresses ferroptosis and promotes lung cancer progression. These findings contribute to the new intervention and treatment options for combating the malignant progression of lung cancer.

Importantly, the genetic deletion of Gch1 in YAP/TAZ-deficient cells abolished their ability to protect WT cells, confirming its essential role in this intercellular program. Our findings revealed a Hippo pathway-linked ferroptosis resistance mechanism and suggested that intra-tumoral heterogeneity in YAP/TAZ activity promotes metastatic fitness by enabling the survival of ferroptosis-prone cells via antioxidant signaling.

GCH1 overexpression or ferrostatin-1 treatment reversed GNA regulation of ROS accumulation and mitochondrial membrane potential inhibition. Taken together, these findings confirmed that GNA suppressed the malignant progression of NSCLC by inducing GCH1-mediated ferroptosis.

CAFs acted as a ferroptosis inhibitor to cause DOX resistance of TNBC via histone lactylation-mediated ZFP64 up-regulation and subsequent promotion of GCH1-induced lipid peroxidation inhibition and FTH1-induced intracellular Fe2+ consumption.

In vitro experiments were performed using KYSE-150 cells to investigate the effects of GCH1 knockdown and overexpression on cell proliferation, cisplatin-induced cell death, and ferroptosis...Targeting GCH1 in combination with GPX4 and FSP1 inhibitors may offer a novel therapeutic strategy for overcoming resistance in ESCC. Further studies are warranted to elucidate the involved molecular mechanisms and validate these findings in vivo.

Functionally, overexpression of LUCAT1 facilitated cell proliferation and reduced the occurrence of ferroptosis induced by RSL3 and Erastin, while inhibition of LUCAT1 expression reduced cell proliferation and increased ferroptosis. These results indicated that inhibition of LUCAT1 expression promoted ferroptosis by modulating the downregulation of GCH1, mediated by miR‑34a‑5p. Therefore, the combination of knocking down LUCAT1 expression with ferroptosis inducers may be a promising strategy for lung cancer treatment.

We also verified the relationship between the GCH1 and MKI67 expression by wet experiment. This model has high prediction accuracy in SKCM patients and can provide a reference for clinical treatment.

SIGNIFICANCE: Cisplatin (DDP) is a commonly used chemotherapeutic agent for triple negative breast cancer (TNBC), but its efficacy can be limited by chemoresistance. This study aimed to unravel the molecular mechanism of SR-rich splicing factor 1 (SRSF1) in DDP chemosensitivity of TNBC cells.

Additionally, high GCH1 corelated with poor breast cancer survival. Together, this study reveals an enzyme-independent oncogenic role of GCH1, presenting it as a potential target for therapeutic development.

This phenomenon could be mediated through direct cytotoxic effects, inhibition of cell proliferation and migration in association with reduction in Gch1 and Spr genes expression, angiogenesis and mitosis rate, and necrosis augmentation. The preliminary data obtained from the present study need to be investigated on a larger scale and can be used as a pilot for further studies on the biology of cancer development.