The caspase-2 paradox in liver polyploidy and cancer risk
Date
2026
Authors
Dorstyn, L.
Kumar, S.
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Journal article
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EXO - Beyond the Cell, 2026; 1-8
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Loretta Dorstyn, Sharad Kumar
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Abstract
Caspase-2 is a key genome-surveillance protease that functions to kill or arrest cells with abnormal chromosome content, via PIDDosome-dependent and -independent mechanisms. However, this surveillance function presents a biological paradox in the liver, where physiological polyploidy, is essential for organogenesis, genomic buffering and adaptive stress responses to maintain liver homeostasis. While short-term caspase-2 loss promotes adaptive polyploidy, our recent work demonstrates that prolonged caspase-2 deficiency drives pathogenic hyperploidy, fuelling chronic inflammation, and increased age-associated hepatocellular carcinoma in mice. These findings underscore the need for tight ploidy control in the maintenance of liver homeostasis. They also highlight potential risks for therapeutic targeting of caspase-2 in fatty liver disease and suggest that pathways governing lipid metabolism also influence long-term tumour surveillance mechanisms. This perspective discusses caspase-2 as a guardian of hepatic genome integrity, and the dual, context-dependent roles of polyploidy in liver physiology and metabolic liver disease.
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© The Author(s) 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.