Figure 1. Necroptosis and ferroptosis: converging pathways and dual inhibition. (IMAGE)
Caption
Necroptosis and ferroptosis: converging pathways and dual inhibition. Necroptosis is a kinase-driven, inflammatory form of regulated necrosis mediated by the RIPK1/RIPK3/MLKL signaling axis. Following stimulation by TNF cytokines, DAMPs, viral infection, or chemical stress, RIPK1 and RIPK3 assemble the necrosome, leading to phosphorylation and oligomerization of MLKL. Activated MLKL translocates to the plasma membrane, where it disrupts membrane integrity and promotes necro-inflammatory release of intracellular DAMPs. Ferroptosis is a regulated necrotic cell death driven by iron-dependent lipid peroxidation. Accumulation of intracellular Fe2+ and ROS promotes peroxidation of PUFA-containing phospholipids when antioxidant defense systems centered on GPX4 and FSP1 fail. The resulting lipid peroxide accumulation destabilizes cellular membranes and ultimately triggers catastrophic membrane damage. Redox imbalance and increased levels of ROS can potentiate both necroptotic and ferroptotic processes. In addition, the molecular chaperone HSP90 modulates these pathways, for example by facilitating chaperone-mediated autophagic degradation of GPX4 during ferroptosis. The dual inhibitory activity of NecroFerrins and the mechanism of action of RIPROStatins are schematically illustrated in the two boxes on the right side of the figure. Adapted from Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). DAMPs: damage-associated molecular patterns; ROS: reactive oxygen species; PUFA: polyunsaturated fatty acid; RIPK: receptor-interacting protein kinase; MLKL: mixed lineage kinase domain-like pseudokinase; TNF: tumor necrosis factor; GPX4: glutathione peroxidase 4; FSP1: ferroptosis suppressor protein 1.
Credit
© Claire Delehouzé*, Stéphane Bach* 2027. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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