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

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.