Abstract
Regulated cell death is a hallmark of inflammatory liver disease, and its intensity influences disease progression and severity. However, it is now clear that the form of cell death could also have an important role. In addition to apoptosis, various forms of regulated necrosis are increasingly reported to contribute to inflammatory liver disease due to their lytic nature. In this Review, we discuss the key regulatory molecules that govern regulated necrosis pathways and summarize our current understanding of the involvement of necroptosis, pyroptosis and ferroptosis in liver injury in preclinical murine models of acute and chronic liver disease and liver cancer development. Furthermore, we highlight the existing controversies and knowledge gaps regarding the relevance of these cell death modalities in hepatocytes and non-hepatocytic liver cells as well as the emerging mechanisms controlling these pathways. Finally, we discuss efforts to specifically modulate these regulated cell death pathways in liver disease and hepatocarcinogenesis in the attempt to prevent liver disease progression or to elicit more potent antitumour immune responses. Outstanding issues and methodological advances that will help to translate preclinical findings into therapeutic applications are also presented.
Key points
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Regulated cell death (RCD) is a hallmark of liver disease with stage-dependent, protumorigenic and tumour-suppressive effects.
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Different forms of regulated necrosis (necroptosis, pyroptosis and ferroptosis) have been associated with liver disease progression, but the ability of hepatocytes to execute them remains controversial.
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Activation of RCD might not always entail full cell death execution, as conditions of sublethal activation are starting to emerge.
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Ninjurin 1 (NINJ1) has been identified as a driver of plasma membrane rupture in the final step of multiple lytic RCD modalities.
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RCD inhibition seems to be a promising treatment strategy in the early stages of liver disease.
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RCD induction, particularly regulated necrosis, could be a promising therapeutic approach in liver cancer treatment by reshaping the tumour microenvironment and acting synergistically with immunotherapy.
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Acknowledgements
M.V. was supported by the German Cancer Aid (Deutsch Krebshilfe; 70114893) and the Ministry of Culture and Science of the State of North Rhine-Westphalia (CANTAR: NW21-062E). V.K. was supported by a grant from the research committee of the Medical Faculty of the Heinrich Heine University (grant number 2023-32). Work in the laboratory of P.B. was supported by the Swiss National Science Foundation (grant numbers 310030B_198005, 310030_219286). T.L. was supported by the European Research Council (ERC-CoG 771083: PhaseControl), the German Research Foundation (DFG: 279874820, 461704932 and 440603844), the German Cancer Aid (Deutsch Krebshilfe: 70114893) and the Ministry of Culture and Science of the State of North Rhine-Westphalia (CANTAR: NW21-062E, and MODS: PROFILNRW-2020-107-A). During the preparation of this work, the authors used an artificial intelligence-based tool (perplexity.ai) for the correction of grammar and language. After using this tool/service, the authors reviewed and edited the text as needed and take full responsibility for the content of the published article.
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Vucur, M., Kondylis, V., Broz, P. et al. Regulated necrosis at the crossroads of liver inflammation and cancer development. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01147-8
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DOI: https://doi.org/10.1038/s41575-025-01147-8
