FDX1 promotes elesclomol-induced PANoptosis in diffuse large B-cell lymphoma by activating IRF3/IFN-β signaling

Abstract Background The identification of cuproptosis, a newly defined form of copper-induced cell death, has provided innovative insights for cancer therapy. However, the function and regulatory mechanism of cuproptosis have not been elucidated in diffuse large B-cell lymphoma (DLBCL), which remains a major clinical challenge and requires the development of new therapeutic approaches. Methods By utilizing databases we analyzed the correlation between FDX1 expression and overall survival of DLBCL patients. We performed cell viability assay, 7-AAD/EdU staining and subsequent flow cytometry to explore the role of FDX1 in DLBCL cell apoptosis, cell proliferation and elesclomol (ES)-induced cell death in vitro . Then in vivo FDX1 function was confirmed through animal models. To investigate the underlying mechanisms, RNA-seq, RT-qPCR, Westernblot and tissue microarray (TMA) assays were carried out. Results We found that loss of the mitochondrial matrix reductase FDX1 in DLBCL cells impairs the antitumor effect of elesclomol (ES), which performs its function by transporting excess copper into cells. Overexpressing (OE) FDX1 significantly sensitized DLBCL cells to ES-induced cell death in vitro and enhanced the anticancer activity of ES in vivo . Mechanistically, ES-induced PANoptosis in FDX1-OE cells is dependent on IFN-β. FDX1 promotes the induction of IFN-β by increasing IRF3 phosphorylation in DLBCL cells upon ES treatment. Consistent with this finding, patient cohort analysis revealed that FDX1 expression correlated positively with enhanced IRF3 phosphorylation. Conclusions Our findings are the first to identify the central role of FDX1 in synergizing with ES to activate IFN-β signaling and induce PANoptosis. This knowledge enables us to re-explore the clinical anticancer potential of ES as a novel therapeutic strategy for DLBCL.