RRM2-mediated inhibition of GPX4 ubiquitination: A novel mechanism for ferroptosis suppression and reduced cisplatin sensitivity in small cell lung cancer.

RRM2 is an important regulatory protein in ferroptosis pathways, but its role in small cell lung cancer (SCLC), which is characterized by rapid proliferation, frequent metastasis, and drug resistance, remains unclear. Here, we report that RRM2 is highly expressed in SCLC tissues and has excellent diagnostic potential. In vitro, our experiments demonstrate that knockdown of RRM2 expression significantly inhibited the proliferation, migration, and invasiveness of NCI-H446 and SBC-2 cells, while overexpression had the opposite effect.Furthermore, RRM2 inhibition significantly enhanced the activity of the ferroptosis pathway in SCLC cells. Additional results from mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments indicated that RRM2 directly interacts with peroxiredoxin 6 (PRDX6), and their binding inhibits the ubiquitination of the key ferroptosis protein, glutathione peroxidase 4 (GPX4), thereby inhibiting ferroptosis in SCLC. Ultimately, inhibition of RRM2 decreased the cisplatin IC50 in SCLC cells, and the ferroptosis inhibitor ferrostatin-1 reversed this effect. These findings suggest that RRM2 is involved in the regulation of GPX4 protein ubiquitination in the ferroptosis pathway, thereby inhibiting ferroptosis activity in SCLC and reducing cisplatin sensitivity. Targeting this may improve the efficacy of chemotherapy in SCLC.