Integrated metabolome and transcriptome analysis reveals ferroptosis involvement in cisplatin resistance of esophageal squamous cancer cell

The aim of this study is to investigate the gene biomarkers and metabolites for esophageal squamous cell carcinoma (ESCC) or cisplatin (DDP)-resistance ESCC through integrated analysis of transcriptome and metabolome. A total of 6130 differentially expressed genes (DEGs) and 326 differentially expressed metabolites (DEMs) were identified in KYSE30 compared to HEEC, while compared to KYSE30, there were totally 1179 DEGs and 224 DEMs in KYSE30/DDP. Profile #6 depicted the mRNA characteristics of KYSE30 obviously. Genes in profile #6 were mainly involved in platinum drug resistance, ferroptosis, and glutathione metabolism. In addition, the associated TCGA dataset identified APOBEC3B as a critical gene involved in inhibiting ferroptosis by activating PD-L1 to suppress CD8⁺T cells. In vitro experiments demonstrated that knockdown of APOBEC3B enhanced ferroptosis and inhibited the glutathione metabolism signaling pathway in KYSE30/DDP. Moreover, in vivo experiments further confirmed that knockdown of APOBEC3B suppressed PD-L1, thereby activating CD8⁺T cells and promoting ferroptosis. These findings indicate the critical role of ferroptosis and glutathione metabolism in the development and progression of ESCC. Meanwhile, APOBEC3B may serve as a promising therapeutic target for cisplatin-resistant ESCC cells.