Redox destabilization by ibrutinib promotes ferroptosis in diffuse large B-cell lymphoma (DLBCL).

Diffuse large B-cell lymphoma (DLBCL) exhibits marked clinical heterogeneity and frequent treatment resistance, particularly in molecularly defined high-risk subtypes such as ABC-DLBCL. While current therapies largely rely on apoptosis induction, non-apoptotic cell death pathways remain underexplored in hematologic malignancies. Here, we identify ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated necrosis, as an effective baseline in additive therapy with ibrutinib for the treatment of DLBCL. Transcriptomic and lipidomic analyses revealed that DLBCL cells, despite lacking overt enrichment of polyunsaturated fatty acids (PUFAs), display elevated expression of the core ferroptosis protective machinery. Inhibition of GPX4 induced rapid and selective lipid ROS accumulation and cell death across a panel of human and murine DLBCL cellular models irrespective of subtype. Notably, the BTK inhibitor and clinical compound ibrutinib showed additive effects with GPX4 inhibition, even at concentrations below its cytotoxic threshold, expanding its therapeutic relevance beyond BTK inhibition. Mechanistically, we uncover two activities of ibrutinib to enhance ferroptosis sensitivity: First, chemical scavenging of glutathione and second the inhibition of GPX4 protein expression via translational repression. Thereby, our findings define ferroptosis as a basis for additive therapy in combination with ibrutinib in DLBCL and reveal a previously unrecognized role for ibrutinib in directly modulating anti-oxidant defense.