The roles of IDH2 and glutathione metabolism in cetuximab resistance in head and neck squamous cell carcinoma investigated by metabolomics and transcriptomics

Cetuximab resistance is a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC). In this study, cetuximab-resistant HNSCC cell lines were established, and untargeted metabolomics was used to detect differences in metabolite profiles between sensitive and resistant cell lines. It was found that glutathione metabolism significantly differed between the sensitive and resistant lines. Combining these findings with transcriptome data, correlation analysis of metabolites revealed that IDH2 regulated glutathione metabolism and contributed to cetuximab resistance in FaDu cells. In vitro experiments showed that IDH2 was highly expressed in FaDu-CR cells, and IDH2 knockdown significantly enhanced the sensitivity of FaDu and FaDu-CR cells to cetuximab. IDH2 knockdown reduced GSH levels and GPX4 expression in FaDu and FaDu-CR cells under cetuximab treatment, while increasing lipid ROS levels. In vivo experiments demonstrated that IDH2 knockdown decreased the tumorigenic ability of FaDu-CR cells in nude mice treated with cetuximab, as well as reduced GPX4 and Ki67 levels in tumor tissues. In conclusion, IDH2 regulated glutathione metabolism and contributed to cetuximab resistance in HNSCC. This study explores strategies to ameliorate cetuximab resistance in HNSCC preclinical models, providing new insights for reversing cetuximab resistance in HNSCC.