PANoptosis Mechanisms in Immune Response and Disease

PANoptosis is a unique form of programmed cell death that integrates features of pyroptosis, apoptosis and necroptosis into a single coordinated response. It is driven by the assembly of a multiprotein PANoptosome complex that recruits sensors such as ZBP1 and key effectors including caspases and receptor-interacting kinases. By orchestrating multiple death pathways simultaneously, PANoptosis circumvents pathogen-mediated inhibition of individual routes and amplifies inflammatory signalling. This mechanism contributes to host defence against infection, shapes the tumour immune microenvironment and influences the progression of autoinflammatory and neurodegenerative diseases. Dysregulation of PANoptosis can exacerbate inflammatory pathology, while targeted modulation offers a promising avenue for therapeutic intervention in sepsis, cancer and sterile inflammatory disorders.

Research from Nature Portfolio

Recent studies have identified the nerve injury-induced protein NINJ1 as a critical executioner of PANoptosis under infection and heat-stress conditions. Genetic ablation of NINJ1 in murine models reduces inflammatory cell death and lethality by preventing pore formation downstream of caspase-1, caspase-8, caspase-11 and RIPK3. Complementary work has uncovered alternative apoptotic pathways activated by caspase-1 in cells lacking gasdermin D. In such contexts, caspase-1 triggers the Bid–caspase-9–caspase-3 axis, revealing a flexible execution phase that can switch between lytic and apoptotic outcomes. Together, these findings clarify the molecular diversity of PANoptosis and suggest that blocking specific executioners may attenuate harmful inflammation without abrogating host defence.

PANoptosis Mechanisms in Immune Response and Disease publication trend

The graph below shows the total number of articles in panoptosis mechanisms in immune response and disease across all publications each year (not limited to Nature Index journals).

Technical terms

PANoptosis: A coordinated form of programmed cell death combining pyroptosis, apoptosis and necroptosis under the regulation of a multi-protein PANoptosome.

PANoptosome: A cytoplasmic multiprotein complex that assembles sensors and effectors to trigger PANoptosis.

Pyroptosis: An inflammatory cell death mediated by inflammasome activation and gasdermin-induced membrane pores.

Apoptosis: A non-inflammatory, caspase-dependent cell death characterised by membrane blebbing and DNA fragmentation.

Necroptosis: A programmed necrosis executed by receptor-interacting protein kinases (RIPK1/RIPK3) and MLKL pore formation.

References

1. NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress. Nature Communications (2024).
2. Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis. Experimental & Molecular Medicine (2023).
3. Current evidence and therapeutic implication of PANoptosis in cancer. Theranostics (2024).
4. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cellular & Molecular Immunology (2021).
5. Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis). Frontiers in Cellular and Infection Microbiology (2020).
6. Caspase-1 initiates apoptosis in the absence of gasdermin D. Nature Communications (2019).