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PANoptosis as a drug discovery framework: integrating cell death architecture with clinical translation

Genes & Immunity (2026)Cite this article

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Abstract

Programmed cell death pathways—apoptosis, pyroptosis, and necroptosis—were long regarded as discrete entities, yet mounting evidence reveals their convergence in PANoptosis, a unified inflammatory death program orchestrated by supramolecular PANoptosome complexes. By integrating upstream sensors (ZBP1, AIM2, NLRP3, Pyrin), scaffolding adaptors (ASC, RIPK1, FADD), and executioners (caspase-1/8, RIPK3–MLKL, gasdermins), PANoptosis operates as a fail-safe against pathogens and oncogenic stress, but also drives immunopathology in sterile injury, sepsis, cancer, and neurodegeneration. This review synthesizes recent advances in the molecular architecture of PANoptosis, highlighting cross-regulatory redundancies, novel modulators, and post-translational checkpoints that expand therapeutic opportunities. We provide an evidence-graded framework for pharmacological intervention, spanning small-molecule inhibitors (RIPK1, RIPK3, MLKL, caspases, NLRP3, gasdermins), biologics (IL-1β, IL-18, TNF antagonists), and nucleic acid therapeutics, with reference to active and completed clinical trials. Emphasis is placed on the Clinical Polarity and Timing Model, which distinguishes contexts where PANoptosis should be induced (apoptosis-resistant tumors) versus restrained (cytokine storm, ischemia–reperfusion injury). Emerging biomarker panels—including phosphorylated RIPK3/MLKL, gasdermin fragments, and inflammasome-derived cytokines—offer tools for patient stratification and real-time pharmacodynamic monitoring. Finally, we explore the drug discovery frontier, from covalent GSDMD antagonists and CNS-penetrant RIPK1 inhibitors to synthetic biology approaches capable of confining PANoptotic modulation to defined tissues. By integrating mechanistic insights with translational pharmacology, this review positions PANoptosis as both a therapeutic target and an adjuvant framework, outlining how its selective modulation could transform the management of infectious, inflammatory, oncologic, and neurodegenerative diseases.

Schematic representation of major human disease categories associated with dysregulated PANoptosis.

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Fig. 1: Schematic overview of PANoptosis.
Fig. 2: Pathogen-driven initiation of PANoptosis in infectious diseases.
Fig. 3: Intermittent hypoxia integrates mitochondrial dysfunction and ER stress with PANoptosis.
Fig. 4: Regulatory networks controlling PANoptotic signaling during ischemia–reperfusion injury and acute organ failure.
Fig. 5: Small-molecule inducers of PANoptosis via distinct signaling pathways.

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Authors and Affiliations

  1. Kusuma School of Biological Sciences Indian Institute of Technology Delhi, Delhi, India

    Mohit Bhardwaj & Saurabh Upadhyay

  2. Department of Biosciences, Jamia Millia Islamia, New Delhi, India

    Kirti Upmanyu

  3. St. Jude Children’s Research Hospital, Memphis, TN, USA

    Saurabh Upadhyay

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  1. Mohit Bhardwaj
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Mohit Bhardwaj contributed to conceptualization, methodology, investigation, data curation, and writing—original draft. Kirti Upmanyu contributed to conceptualization, methodology, investigation, data curation, and writing—original draft. Saurabh Upadhyay contributed to conceptualization, supervision, and writing—review & editing.

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Bhardwaj, M., Upmanyu, K. & Upadhyay, S. PANoptosis as a drug discovery framework: integrating cell death architecture with clinical translation. Genes Immun (2026). https://doi.org/10.1038/s41435-026-00388-0

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