PT  - JOURNAL ARTICLE
AU  - Mate Maus
AU  - Vanessa López-Polo
AU  - Miguel Lafarga
AU  - Mònica Aguilera
AU  - Eugenia De Lama
AU  - Kathleen Meyer
AU  - Anna Manonelles
AU  - Anna Sola
AU  - Cecilia Lopez Martinez
AU  - Ines López-Alonso
AU  - Fernanda Hernandez-Gonzales
AU  - Selim Chaib
AU  - Miguel Rovira
AU  - Mayka Sanchez
AU  - Rosa Faner
AU  - Alvar Agusti
AU  - Neus Prats
AU  - Guillermo Albaiceta
AU  - Josep M. Cruzado
AU  - Manuel Serrano
TI  - Iron accumulation drives fibrosis, senescence, and the senescence-associated secretory phenotype
AID  - 10.1101/2022.07.29.501953
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.29.501953
4099  - http://biorxiv.org/content/early/2022/08/01/2022.07.29.501953.short
4100  - http://biorxiv.org/content/early/2022/08/01/2022.07.29.501953.full
AB  - 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). However, the mechanisms involved in the conversion of damaged cells into senescent cells remain incompletely understood. Here, we report that multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries, through the release of iron, are efficient in triggering senescence and fibrosis. Interestingly, the accumulation of iron is an intrinsic property of senescent cells that does not require an abnormal surge in extracellular iron. Upon damage, cells initiate an iron accumulation response with abundant ferritin-bound iron within lysosomes and high levels of labile iron, the latter being a main driver of senescence-associated ROS and SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging (MRI) is a powerful non-invasive method to assess fibrotic burden in the kidneys of mice and patients with renal fibrosis. Our findings establish a central role for iron accumulation in senescence and fibrogenesis.Competing Interest StatementM.S. is a shareholder of Senolytic Therapeutics, Life Biosciences, Rejuveron Senescence Therapeutics, and Altos Labs and is an advisor to Rejuveron Senescence Therapeutics and Altos Labs. The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.