Targeting ferroptosis has emerged as a therapeutic vulnerability in combating therapy-resistant and dedifferentiating cancers. Therefore, new in vivo active ferroptosis-inducing compounds are urgently needed. Here we introduce a novel compound class of ferroptosis inducing agents, called icFSP1, which targets ferroptosis suppressor protein-1 (FSP1), one of the guardians of ferroptosis. Unlike our first reported FSP1-specific inhibitor iFSP1 (Doll et al., Nature 2019), icFSP does not inhibit FSP1 directly, but causes membrane detachment and phase separation of FSP1. Phase separation is a physicochemical process that is involved in numerous cellular processes including cell signaling and transcriptional regulation and is known to play a role in neurodegenerative disease and cancer. We further demonstrate that icFSP1 impairs tumor growth in vivo by inducing phase separation of FSP1. Our study thus provides the basis for targeting FSP1 as a future approach to treat certain cancers by triggering ferroptosis (Nakamura et al., Nature 2023)(see also "New Approach in Cancer Therapy With Innovative Mechanism-of-Action for Ferroptosis Induction").

Building on our earlier discovery of a rare GPX4 mutation (R152H) that triggers the ultrarare disorder SMDS and early childhood neurodegeneration, we now show that ferroptosis may be the dominant cell-death pathway underlying Alzheimer’s and other neurodegenerative diseases. We also uncover the long-sought mechanism by which the key ferroptosis regulator GPX4 positions itself on lipid membranes to shield them from deleterious lipid peroxidation. Akin to a surfboard, GPX4 loosely docks onto lipid bilayers via an unusual fin-loop structure, gliding across their surface to scavenge harmful peroxides in phospholipids. Mice lacking neuronal GPX4 or expressing the R152H variant in the cortex develop profound cortical atrophy, widespread neuroinflammation, and proteomic signatures strikingly reminiscent of Alzheimer’s and other neurodegenerative disorders. Together, these insights lay the groundwork for next-generation anti-ferroptotic therapies for Alzheimer’s and beyond (Lorenz, Wahida, Bostock, Seibt, Santos Dias Mourão et al. Cell 2025)(see also "Single Enzyme Failure Found to Drive Neuron Loss in Dementia").

The trace element selenium is essential for the expression of a small subset of proteins, known as selenoproteins, which incorporate selenium in the form of selenocysteine, typically within their active sites. Among these proteins is GPX4, now widely regarded as the "guardian of ferroptosis" due to its unique role in scavenging peroxides in cell membranes. Peroxiredoxin-6 (PRDX6) is another cell-protective enzyme reported to have dual functions by acting as a phospholipase and reducing phospholipid hydroperoxides, similar to GPX4. In our recent study, we demonstrate that PRDX6 does not function as a peroxidase but rather as an intracellular selenium carrier, facilitating the expression of selenoproteins, including GPX4. Knockout of PRDX6 sensitizes cancer cells to ferroptosis and significantly impairs tumor growth in vivo. Moreover, the loss of PRDX6 in mice reduces the expression of selenoproteins, particularly in the brain. These findings reveal PRDX6 as the missing link in the synthesis of selenocysteine-loaded tRNA, which is essential for selenoprotein biosynthesis (Ito et al., Mol Cell 2024)(see also “Novel Selenium Carrier Protein Regulates Ferroptosis in Cancer and Brain”).