Study establishes iron accumulation as a driver of pathological senescence and fibrosis

Fibrosis is associated with various chronic and life-threatening conditions, including pulmonary fibrosis, liver cirrhosis, kidney disease, and cardiovascular diseases, among others. These conditions collectively contribute to a substantial portion of mortality in developed countries, making fibrotic diseases a critical health problem requiring attention, research, and innovative approaches for diagnosis and treatment.

Scientists at IRB Barcelona's Cellular Plasticity and Disease lab, led by Dr. Manuel Serrano, have now described the pivotal role of iron accumulation in the development of fibrotic diseases. The researchers have studied the link between iron accumulation, senescence (a phase where cells neither divide nor die) and the Senescence-Associated Secretory Phenotype (SASP)-;a communication system in ageing cells that prompts them to release harmful molecules. SASP has been associated with various age-related diseases, including fibrosis.

In this work, published in the journal Nature Metabolism, researchers show the potential of iron detection via magnetic resonance imaging (MRI) for non-invasive assessment of fibrotic burden in patients with renal fibrosis. Additionally, the team uncovers the potential of chemical compounds able to remove the accumulated iron, such as deferiprone (a clinically approved drug) to prevent fibrosis, thereby pointing to a new approach for treating fibrotic diseases.

Our study establishes iron accumulation as a clinically exploitable driver of pathological senescence and fibrosis and paves the way for new strategies in the early detection and treatment of fibrotic diseases."

Dr. Mate Maus, Lead Author, IRB Barcelona

Dr. Maus is the leading author of the study, together with Dr. Serrano, and an IRB Barcelona alumnus. He is currently leading the Aging and Cancer lab at the Vall d'Hebron Institute of Oncology (VHIO), in Barcelona, where he continues investigating age-related metabolic changes that promote chronic diseases and cancer.

Systemic iron metabolism

Iron accumulation had previously been reported in association with several fibrotic disorders. On the basis of the findings of this study, the scientists suggest it might be a common feature of most fibrotic diseases. This research highlights two distinct roles of iron in fibrogenesis. First, it shows that excessive extracellular iron can initiate fibrogenesis. For instance, this may occur in fibrotic diseases associated with small vascular injuries, where iron release from the vasculature may be a constant trigger for fibrogenesis Second, the study indicates that iron accumulation is an intrinsic characteristic of senescent cells, even under normal levels of extracellular iron. The accumulation of iron is a key event driving the SASP and its pro-fibrotic effects on the surrounding tissue.

Halting fibrosis

By addressing iron accumulation in senescent cells, the researchers aim to alleviate the SASP and, consequently, halt the progression of fibrosis. "Although these findings mark a significant step forward in our understanding of fibrotic diseases, further research and clinical validation are crucial before translating these insights into tangible treatments," concludes Dr. Serrano.

This research project was carried out in collaboration with Dr. Josep Maria Cruzado's laboratory at IDIBELL/UB, the Biostatistics and Bioinformatics Core Facility, led by Dr. Camille Stephan-Otto Attolini and the Histopathology Core Facility led by Dr. Neus Prats, both at IRB Barcelona; Dr. Mayka Sánchez, from the Universitat Internacional de Catalunya (UIC); Dr. Alvar Agustí, from the Hospital Clinic/IDIBAPS; and Dr. Miguel Lafarga, from the Universidad de Cantabria-IDIVAL. Researchers from the Functional Genomics Core Facility at IRB Barcelona, the University of Oviedo and CNIO also contributed to the study.

Dr. Manuel Serrano is currently working at Altos Labs, Cambridge, United Kingdom.

The research received funding from the European Union's Horizon 2020 research and innovation programme, the Spanish Ministry of Science and Innovation (MCIN), "la Caixa" Foundation, the European Regional Development Fund (ERDF), the European Research Council (ERC), the Instituto de Salud Carlos III and the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de Catalunya.