biostudies-literatureDondelinger YStichting Tegen KankerVlaams Instituut voor BiotechnologieFonds Wetenschappelijk OnderzoekUniversiteit GentUniversity of Ghent755https://www.ebi.ac.uk/biostudies/studies/S-EPMC10657445biostudies-literatureUnknown14(11)Plasma membrane permeabilization (PMP) is a defining feature of regulated necrosis. It allows the extracellular release of damage-associated molecular patterns (DAMPs) that trigger sterile inflammation. The pore forming molecules MLKL and GSDMs drive PMP in necroptosis and pyroptosis, respectively, but the process of PMP remains unclear in many other forms of regulated necrosis. Here, we identified NINJ1 as a crucial regulator of PMP and consequent DAMP release during ferroptosis, parthanatos, H₂O₂-induced necrosis and secondary necrosis. Importantly, the membrane-permeabilizing function of NINJ1 takes place after the metabolic death of the cells and is independent of the pore-forming molecules MLKL, GSDMD and GSDME. During ferroptosis, NINJ1 acts downstream of lipid Cell death & diseaseNINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis.PMC1065744501G001233G046420iBOF ATLANTIS grant 01IB39203G044518WMethusalem grant BOF16/MET_V/007G.0B96.20NiBOF ATLANTIS 01IB3920BOF22/MET_V/007G.0B71.18NG.0A93.22NEOS CD-INFLADIS 3G0I5722F/2020/1505G.0C76.18NPriem DDondelinger YHuyghe JVandenabeele PBertrand MJMDelanghe TfalseNINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis.Plasma membrane permeabilization (PMP) is a defining feature of regulated necrosis. It allows the extracellular release of damage-associated molecular patterns (DAMPs) that trigger sterile inflammation. The pore forming molecules MLKL and GSDMs drive PMP in necroptosis and pyroptosis, respectively, but the process of PMP remains unclear in many other forms of regulated necrosis. Here, we identified NINJ1 as a crucial regulator of PMP and consequent DAMP release during ferroptosis, parthanatos, H₂O₂-induced necrosis and secondary necrosis. Importantly, the membrane-permeabilizing function of NINJ1 takes place after the metabolic death of the cells and is independent of the pore-forming molecules MLKL, GSDMD and GSDME. During ferroptosis, NINJ1 acts downstream of lipid 2023-01-01T00:00:00Z2023 Nov2026-07-15T00:22:33.685Z2025-04-06T08:14:20.201ZS-EPMC106574453798041210.1038/s41419-023-06284-z