RRM2/GCH1 signaling decreased cisplatin sensitivity in cervical cancer by modulating the ferroptosis process

Cisplatin-based chemotherapy serves as a fundamental approach in the treatment of cervical cancer; however, its effectiveness is often hindered by the development of drug resistance, which presents a significant obstacle in clinical practice.

Differentially expressed genes (DEGs) related to ferroptosis in cervical cancer were examined compared to healthy controls, using data from the Gene Expression Omnibus (GEO) database and the ferroptosis database (FerrDb V2). Lipid peroxidation, ferrous ion (Fe²⁺) concentration, and reactive oxygen species (ROS) were examined. In vitro and in vivo studies were carried out to explore the influence of Ribonucleotide reductase M2 (RRM2) on the effectiveness of cisplatin chemotherapy.

We identified an aggregate of 4,385 statistically significant DEGs, among which 122 genes were related to ferroptosis. Moreover, the ferroptosis-related gene RRM2 was notably overexpressed in cervical cancer and demonstrated remarkable sensitivity and specificity for diagnosing cervical cancer. Additionally, the expression levels were inversely correlated with the outcomes of patients with cervical cancer. Furthermore, RRM2 silencing increased cervical cancer cell ferroptosis and enhanced the efficacy of cisplatin treatment in vitro and in vivo. Finally, our experiments established a positive association between RRM2 and the classical ferroptosis inhibition factor GTP cyclohydrolase 1 (GCH1) by immunofluorescence and immunoblotting.

RRM2 plays roles in the evaluation and outcome prediction of cervical cancer, potentially impacting cisplatin sensitivity through regulation of ferroptosis. This investigation provides novel insights into the tumorigenic functions of RRM2, highlighting its potential use as a prognostic biomarker in cervical carcinoma.