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NLRP3 Inflammasome Roles in PANoptosis, Disease

August 20, 2025
in Medicine
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The landscape of programmed cell death has undergone a transformative expansion with the discovery of PANoptosis, a unique cell death modality that integrates features from pyroptosis, apoptosis, and necrosis. First proposed in 2019 by Professor Kanneganti’s team, this novel form of cell demise is orchestrated through specialized multiprotein complexes termed PANoptosomes. The emergence of PANoptosis challenges traditional views that rigidly categorized cell death pathways, revealing a highly interconnected network capable of executing diverse immunological and pathological functions. Recent research spotlighted the crucial involvement of the NLRP3 inflammasome as a central regulatory hub in these complexes, significantly broadening our understanding of immunological defense mechanisms and disease pathogenesis.

At the molecular core of PANoptosis lies the formation of PANoptosome complexes, which emerge upon sensing specific internal or external stressors through intracellular sensor molecules. Proteins such as Z-DNA-binding protein 1 (ZBP1), AIM2, receptor-interacting protein kinase 1 (RIPK1), NLR family pyrin domain-containing 12 (NLRP12), and NLRC5 detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), triggering the assembly of varied PANoptosomes. Among these, NLRP3 inflammasome plays an indispensable role, participating in several PANoptosome configurations, including those associated with ZBP1, RIPK1, NLRP12, and NLRC5, linking the inflammasome machinery to broad cell death phenotypes.

Initial studies, particularly in viral infection models like influenza A virus (IAV), elucidated the ZBP1-PANoptosome as a prototypical example where the sensor ZBP1 detects viral RNA via its Zα2 domain. In this complex, NLRP3 inflammasome components interact with caspase-1 and the adaptor protein ASC to promote pyroptosis. Simultaneously, the complex mobilizes necroptotic and apoptotic kinases, including RIPK3 and caspase-8, resulting in a sequential activation cascade culminating in PANoptosis. This sophisticated signaling network exemplifies how cells coordinate immune defense and inflammatory responses through orchestrated death pathways.

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The participation of caspase-6 in promoting ZBP1 and RIPK3 binding further underscores the complexity of PANoptosome regulation. This interaction bolsters the assembly of the ZBP1-PANoptosome and amplifies downstream cell death signaling. The intricate molecular choreography involving caspase family members and RIP kinases reveals the delicate balance between host defense mechanisms and inflammatory control within infected and damaged tissues, emphasizing the therapeutic potential of modulating these interactions in infection and inflammatory disorders.

Besides the ZBP1-PANoptosome, the RIPK1-PANoptosome represents another crucial assembly, especially noted under conditions of TAK1 inhibition—a kinase pivotal for maintaining NLRP3 inflammasome quiescence and cellular homeostasis. In scenarios such as bacterial infection with Yersinia species or in the presence of lipopolysaccharide (LPS), RIPK1 collaborates with NLRP3, RIPK3, and caspase-8 to form a complex that drives PANoptosis. This ensemble exemplifies how disruption of cellular checkpoints can elicit catastrophic cell death, thereby impacting host-pathogen interactions and inflammatory disease progression.

In parallel, the NLRP12-PANoptosome complex has been characterized following stimulation with heme and pathogen-derived molecules. This complex comprises NLRP12, NLRP3, ASC, caspase-1, RIPK3, and caspase-8. Interestingly, while NLRP3 enhances the integrity of this complex, its absence does not preclude formation, highlighting functional redundancy and flexibility within PANoptotic signaling. The implications for diseases characterized by heme release, such as hemolytic anemias and certain inflammatory disorders, are profound, linking PANoptosis to pathophysiological tissue damage.

Adding a layer of enigmatic complexity, NLRC5 has recently been identified as a sensor forming its own PANoptosome. This complex includes NLRC5, NLRP3, NLRP12, caspase-8, and associated molecules. The NLRC5-PANoptosome has been implicated in bacterial infections and in the recognition of various PAMPs and DAMPs, culminating in pronounced inflammatory cell death and tissue damage. The discovery of this complex broadens the functional repertoire of NLR family sensors beyond canonical inflammasome activity, opening new avenues for investigating inflammatory disease mechanisms.

The centrality of the NLRP3 inflammasome in these PANoptosome assemblies is particularly noteworthy. Traditionally viewed as a prototypical pyroptotic inflammasome sensor, NLRP3 herein assumes a more versatile role, not only orchestrating classical inflammasome activation and caspase-1-driven pyroptosis but also coordinating crosstalk among apoptosis and necroptosis pathways through PANoptosome formation. This dual functionality highlights the inflammasome’s importance in immune surveillance and underscores its potential as a therapeutic target in diseases driven by dysregulated cell death.

PANoptosis represents a convergence point of multiple programmed cell death pathways, facilitating a tailored response to diverse stimuli such as microbial invasion, tissue damage, oncogenic transformation, and inflammatory signaling. This integrative death mechanism enables cells to deploy a comprehensive defense strategy, balancing elimination of invaders with controlled inflammation. The molecular plasticity inherent in PANoptosis, mediated through sensor-specific PANoptosome complexes, provides the immune system with versatile tools to maintain homeostasis across various pathological contexts.

The physiological and pathological implications of PANoptosis extend across multiple disease arenas, including infectious diseases, autoimmune disorders, inflammatory syndromes, and cancer. Dysregulated PANoptosis can exacerbate tissue injury, perpetuate chronic inflammation, or, conversely, facilitate anti-cancer responses by eliminating malignant cells. Understanding the triggers, molecular players, and regulatory checkpoints within PANoptosis is therefore pivotal for developing novel interventions that modulate immune cell death, enhancing therapeutic efficacy and minimizing collateral damage.

Research exploring PANoptosis has also uncovered the requirement of stimulus-specific and context-dependent formation of distinct PANoptosomes. It is hypothesized that beyond the known complexes involving ZBP1, RIPK1, NLRP12, and NLRC5, other yet-unidentified sensors might contribute to tailored PANoptotic responses under unique physiological or pathological conditions. This proposition hints at an expansive and intricate universe of intracellular sensor networks capable of dynamically regulating cell fate decisions.

At the biochemical level, downstream effectors activated by PANoptosomes include caspase-1-mediated cleavage of gasdermin D (GSDMD), driving pyroptotic membrane pore formation; caspase-3/7-mediated cleavage of gasdermin E (GSDME), facilitating apoptotic features; and RIPK3-induced phosphorylation of MLKL, triggering necroptotic membrane permeabilization. The coordination of these molecular events leads to irreversible plasma membrane damage, inflammatory cytokine release, and the distinctive hallmarks of PANoptosis, which amalgamate pyroptosis, apoptosis, and necrosis into a singular, interrelated process.

The discovery of PANoptosis revolutionizes our molecular understanding of the inflammasome complexes, revealing an interconnected death platform where NLRP3 serves as both a canonical immune sensor and a pivotal assembly factor. This dual identity expands the inflammasome’s role beyond merely initiating inflammation, positioning it as a critical determinant in immunological homeostasis and disease pathology. The potential to pharmacologically target components within PANoptosomes offers promising avenues for therapeutic development against infections, inflammatory diseases, and cancer.

Given the multifaceted nature of PANoptosis, ongoing research endeavors aim to delineate precise molecular mechanisms governing the initiation, regulation, and execution of this cell death modality. The interplay among inflammasome sensors, caspases, RIP kinases, and gasdermins embodies a sophisticated network that cells leverage to adapt and respond to environmental challenges. Deciphering these complex signal transduction pathways is essential for harnessing their therapeutic potential, particularly in diseases marked by aberrant inflammation and immune dysregulation.

In conclusion, PANoptosis represents a groundbreaking concept integrating cellular demise pathways through specialized inflammasome-associated complexes. With NLRP3 at its center, PANoptosis orchestrates a multifactorial response to pathogen invasion, cellular stress, and oncogenic signals. Future studies unraveled the intricacies of PANoptosome assembly, regulation, and substrate specificity will be critical not only for understanding innate immunity but also for pioneering innovative treatment strategies targeting inflammatory and degenerative diseases worldwide.


Subject of Research: Diverse functions of the NLRP3 inflammasome in PANoptosis and associated disease mechanisms.

Article Title: Diverse functions of NLRP3 inflammasome in PANoptosis and diseases.

Article References:
Jiang, Y., Qiang, Z., Liu, Y. et al. Diverse functions of NLRP3 inflammasome in PANoptosis and diseases. Cell Death Discov. 11, 389 (2025). https://doi.org/10.1038/s41420-025-02689-1

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02689-1

Tags: damage-associated molecular patterns responsedisease pathogenesis and cell deathimmunological defense mechanismsmultiprotein complexes in cell deathNLRP3 inflammasome rolesPANoptosis and cell deathPANoptosome complex formationpathogen-associated molecular patterns detectionprogrammed cell death mechanismspyroptosis apoptosis necrosis integrationrecent research on PANoptosisstressor sensing in cells
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