Regulated necrosis at the crossroads of liver inflammation and cancer development

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.