High ferroptosis score activity as a predictor of survival and rituximab response in diffuse large B-cell lymphoma.

e19073 Background: Ferroptosis is an iron-dependent form of cell death linked to redox imbalance, tumor immunity, and therapy sensitivity. In diffuse large B-cell lymphoma (DLBCL), its clinical relevance remains incompletely defined. We evaluated whether ferroptosis activity, quantified by a transcriptomic ferroptosis score (FerroScore), is associated with survival, treatment response, and underlying biological pathways in DLBCL. Methods: Gene expression and clinical data from GSE10846 (n=420) were analyzed. FerroScore was calculated using single-sample GSEA based on 20 canonical ferroptosis regulators (SLC7A11, GPX4, ACSL4, ALOX15, LPCAT3, NCOA4, AIFM2, GCLC, GCLM, FTH1, FTL, TFRC, HMOX1, NFE2L2, KEAP1, SCD, SAT1, PTGS2, CISD1, DPP4). Patients were dichotomized by the median FerroScore. Overall survival (OS) was assessed using Kaplan–Meier and Cox models. Associations with clinical features were evaluated, and pathway enrichment analyses were performed. Prognostic effects were examined separately in R-CHOP and CHOP treated patients. Results: In the GSE10846 cohort, patients with higher FerroScores showed significantly better OS (HR = 0.85, 95% CI 0.72–0.99, p= 0.04). When stratified by treatment, the association persisted among R-CHOP treated patients (p= 0.0004) but not in those treated with CHOP alone, suggesting that ferroptosis activity may enhance the efficacy of rituximab-containing regimens. FerroScore did not correlate significantly with LDH levels or ECOG status but tended to be higher in patients with advanced stage or extranodal involvement. Pathway level analysis revealed that tumors with high FerroScores were enriched for TNF-α/NF-κB signaling, apoptosis, and complement activation, indicating an immune-active, pro-inflammatory phenotype. Conversely, MYC target and KRAS downstream signaling were reduced, consistent with suppression of proliferative and metabolic stress pathways. Among individual genes, SLC7A11, CEBPB, and ERO1A were the most strongly correlated with FerroScore, reflecting a link between oxidative stress regulation and immune activation. Collectively, these findings suggest that ferroptosis-high DLBCL exhibits both inflammatory and stress adaptive molecular traits, which may contribute to improved therapy response and survival. Conclusions: FerroScore provides a transcriptomic measure of ferroptosis activity that captures clinically meaningful heterogeneity in DLBCL. High FerroScore is associated with better survival in R-CHOP treated patients and correlates with immune and apoptotic pathway activation. This study links ferroptosis biology to real-world treatment outcomes, identifying ferroptosis as a potential biomarker of therapy response and disease biology in DLBCL. Future validation needed to support its role in risk stratification and treatment personalization.