SLC1A5 and NUMA1 are potential regulators and therapeutic targets of ferroptosis in diffuse large B-cell lymphoma.

BACKGROUND: Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a potential therapeutic target in various cancers, including diffuse large B-cell lymphoma (DLBCL). This study aimed to identify and characterize ferroptosis-related panel genes with prognostic value in DLBCL. METHODS: Transcriptomic data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were analyzed to identify differentially expressed genes (DEGs) in DLBCL samples. Gene set variation analysis (GSVA) and network topology analysis were performed to identify key ferroptosis-related genes. Lasso regression was utilized to construct a prognostic model based on the identified panel genes. In vitro experiments, including gene silencing, overexpression, and ferroptosis induction, were conducted to evaluate the functional roles of the identified genes, NUMA1 and SLC1A5, in DLBCL cells. RESULTS: A panel of ferroptosis-related genes with prognostic value, including NUMA1 and SLC1A5, was identified in DLBCL samples. Silencing SLC1A5 or overexpressing NUMA1 in DLBCL cells enhanced sensitivity to ferroptosis inducers, increased intracellular labile iron and lipid peroxidation levels, promoted mitochondrial damage, and modulated the expression of key ferroptosis markers. Furthermore, SLC1A5 silencing or NUMA1 overexpression augmented radiation-induced ferroptosis in DLBCL cells. CONCLUSION: NUMA1 and SLC1A5 are potential ferroptosis regulators and therapeutic targets in DLBCL. Silencing the ferroptosis-suppressive transporter SLC1A5 or restoring NUMA1 expression promotes lipid peroxidation and ferroptotic cell death, thereby sensitizing DLBCL cells to ferroptosis and enhancing radiosensitivity-providing a rationale for novel ferroptosis-based therapeutic strategies.