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oai:repisalud.isciii.es:20.500.12105/231002024-11-29T21:25:46Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Maus, Mate author López-Polo, Vanessa author Mateo, Lidia author Lafarga, Miguel author Aguilera, Mónica author De Lama, Eugenia author Meyer, Kathleen author Sola, Anna author Lopez-Martinez, Cecilia author López-Alonso, Ines author Guasch-Piqueras, Marc author Hernandez-Gonzalez, Fernanda author Chaib, Selim author Rovira, Miguel author Sanchez, Mayka author Faner, Rosa author Agusti, Alvar author Diéguez-Hurtado, Rodrigo author Ortega Jimenez, Sagrario author Manonelles, Anna author Engelhardt, Stefan author Monteiro, Freddy author Stephan-Otto Attolini, Camille author Prats, Neus author Albaiceta, Guillermo author Cruzado, Josep M author Serrano, Manuel author 2023-12 Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases. Nat Metab . 2023 ;5(12):2111-2130 https://hdl.handle.net/20.500.12105/23100 38097808 10.1038/s42255-023-00928-2 2522-5812 Nature metabolism Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype.