Polyamines are small molecules naturally present in all cells and are critical in guiding cellular decisions, whereas an alteration in the abundance of these metabolites is invariably observed in pathological scenarios such as cancer or aging. Despite decades of research, the mechanisms through which polyamines control cellular decisions have remained obscure.
A collaborative study published in Nature and led by scientists at CIC bioGUNE, reports the discovery of a mechanism that reformulates our understanding of the actions of polyamines in health and disease.
Using an integrated approach that combined molecular simulations, biochemical and structural analyses, proteomics, and cellular assays, the scientific team identified that these metabolites alter the phosphoproteomic landscape, which has important repercussions for protein function.
They focus on proteins that take part in the control of alternative splicing, a process that alters that repertoire of RNAs and proteins in our cells.
The research team could pinpoint the recognition mode of polyamines on target proteins and demonstrate that this process can be disrupted or potentiated through genetic or pharmacological means. With hundreds of proteins exhibiting potential polyamine-binding motifs, this study opens the door for a renewed perception of polyamine-regulated cellular responses.
Polyamines are overproduced in cancer, and their loss is associated with the process of aging. In turn, inhibiting polyamine metabolism through pharmacological approaches has been evaluated in different cancers, and it is currently employed as a therapeutic strategy in neuroblastoma.
Conversely, dietary polyamine supplementation is posed as an innovative strategy to counteract aging. The findings of Zabala, Pujana and colleagues could contribute to elucidating the effectors of polyamines in these processes, thus helping in the design of next-generation dietary and pharmacological interventions.
The work was led by Dr. Arkaitz Carracedo, Ikerbasque Research Professor, head of the Cancer Cell Signaling and Metabolism Laboratory at CIC bioGUNE (member of BRTA) and group leader in CIBERONC, with Dr. Amaia Zabala-Letona and Dr. Mikel Pujana-Vaquerizo as co-first authors.
This body of work represents an international collaboration involving more than 25 institutions.
Publication details
Arkaitz Carracedo, Polyamine-dependent metabolic shielding regulates alternative splicing, Nature (2026). DOI: 10.1038/s41586-025-09965-1. www.nature.com/articles/s41586-025-09965-1
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