DMF has different mechanisms of action in different subtypes of DLBCL. In the GCB subtype (left), direct succinylation of glutathione (GSH) by DMF leads to GSH depletion, impairing the ability of glutathione peroxidase 4 (GPX4) to detoxify polyunsaturated fatty acids (PUFAs) that have undergone peroxidation. Such damage to plasma membrane lipids results from reactive oxygen species (ROS), produced by enzymes such as arachidonate 5-lipoxygenase (5-LOX), and causes ferroptosis, a caspase-independent form of programmed cell death. DMF does not cause ferroptosis in the ABC subtype of DLBCL (right), but instead inhibits 2 of its distinctive prosurvival signaling pathways. Transcription of target genes by canonical nuclear factor κB (NF-κB), one of the key consequences of “chronic active” signaling by the B-cell receptor (BCR) in ABC-DLBCL, depends on activation by the IKK2 kinase; similarly, activation of the STAT3 transcription factor depends on the kinase JAK1, downstream of autocrine signaling by interleukin-6 (IL-6) and IL-10. DMF inactivates both of these kinases by direct succinylation of critical cysteine residues. See the visual abstract in the article by Schmitt et al that begins on page XXX.