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A pathway of osmotic stress-induced necroptosis

Necroptosis is a form of regulated necrosis in which RIPK3 is activated by binding to RIP homotypic interaction motif (RHIM)-containing proteins. Now, researchers describe a non-canonical pathway of RIPK3 activation that is triggered by osmotic stress and NHE1-mediated cytosol alkalinization. This previously undescribed mechanism of osmotic stress-induced necroptosis might have implications for treating cancer and other diseases.

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Fig. 1: Pathways of RIPK3 activation and necroptosis.


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The authors have received funding from FIS/Fondos FEDER: PI19/00588, PI19/00815, Instituto de Salud Carlos III (ISCIII) RICORS2040 (RD21/0005/0001), Financiado por la Unión Europea – NextGenerationEU and Mecanismo para la Recuperación y la Resiliencia (MRR). A.B.S. has received salary support from the Ramon y Cajal program.

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Correspondence to Alberto Ortiz or Ana B. Sanz.

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A.O. has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, Astrazeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma, and is Director of the Catedra Mundipharma-UAM of DKD and the Catedra Astrazeneca-UAM of CKD and electrolytes. A.B.S. declares no competing interests.

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Ortiz, A., Sanz, A.B. A pathway of osmotic stress-induced necroptosis. Nat Rev Nephrol 18, 609–610 (2022).

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