The role of PANoptosis regulatory networks in acute neurological injury

Zhen Gao

doi:10.1016/j.nbd.2026.107566

The role of PANoptosis regulatory networks in acute neurological injury

2026-08-05

0

OA

AI

Z

Zhen Gao

C

Chengjin Wang

W

Wenjun Yang

Z

Zihui Deng

Y

Yuan Cao

王

王敏 (Min Wang)

Y

Yiqi Wu

S

Shaoqing Shi

L

Lu Wang *

H

Hongjun Kang *

DOI：10.1016/j.nbd.2026.107566

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Abstract

En 中文

Secondary injury following acute neurological insults—including stroke, spinal cord injury(SCI), traumatic brain injury(TBI), and subarachnoid hemorrhage(SAH)—is a major contributor to neuronal death and neuroinflammation; however, the complex molecular mechanisms driving these pathological processes remain poorly understood. The limited efficacy of traditional apoptosis-targeted therapies highlights the need to investigate alternative regulated cell death pathways governed by diverse and intricate regulatory networks. PANoptosis, an emerging form of inflammatory programmed cell death initially proposed to describe the crosstalk among apoptosis, pyroptosis, and necroptosis, is regulated by dynamic molecular complexes, such as the PANoptosome, which orchestrate multiple cell death-associated pathways and contribute to neuronal loss and the amplification of inflammatory responses. This review provides a comprehensive overview of the molecular mechanisms of PANoptosis and its functional roles in acute neurological injury, with a particular emphasis on its pathological regulatory networks associated with ischemic stroke and spinal cord injury. Furthermore, we highlight emerging therapeutic strategies targeting PANoptosis. Recent evidence has identified key molecular mediators, including Z-DNA-binding Protein 1 (ZBP1), receptor-Interacting Protein Kinase 1 (RIPK1), and TGF-β-Activated Kinase 1 (TAK1), which regulate PANoptosome assembly and downstream effector pathways, highlighting their potential as promising therapeutic targets. Inhibition of PANoptosis has been shown to markedly alleviate blood-brain barrier (BBB) disruption and neurological deficits. Additionally, this review addresses the translational challenges and future research directions in targeting PANoptosis, providing a theoretical basis for the development of multi-targeted neuroprotective strategies.

Keywords:

PANoptosis

PANoptosome

Acute neurological injury

Programmed cell death

Multi-targeted therapy

Neuroinflammation

AAV

Adeno-Associated Virus

ACI

Acute Cerebral Infarction

ADCY

Adenylyl Cyclase

AIM2

Absent In Melanoma 2

ASC

Apoptosis-Associated Speck-Like Protein Containing a CARD

BAX

Bcl-2-Associated X Protein

BBB

Blood-Brain Barrier

CAD

caspase-Activated DNase

cGAMP

Cyclic GMP-AMP

cGAS-STING

Cyclic GMP-AMP Synthase – Stimulator of Interferon Genes

DAMPs

Damage-Associated Molecular Patterns

DED

Death Effector Domain

EH

Esculentoside H

EVs

Extracellular Vesicles

FADD

FAS-Associated Death Domain Protein

GSDMD

Gasdermin D

HMGB1

High Mobility Group Box 1

HSF1

Heat Shock Factor 1

IRF1

Interferon Regulatory Factor 1

IRF9

Interferon Regulatory Factor 9

IS

Ischemic Stroke

LAMP2

Lysosome-Associated Membrane Protein 2

Lgals3

Galectin-3 (official gene symbol)

MLKL

Mixed Lineage Kinase Domain-Like Protein

MMP-9

Matrix Metalloproteinase 9

MODS

Multiple Organ Dysfunction Syndrome

MOMP

Mitochondrial Outer Membrane Permeabilization

NAIP

NLR Apoptosis Inhibitory Protein

NBP

DL-3-n-Butylphthalide

NF-κB

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells

NIHSS

National Institutes of Health Stroke Scale

NINJ1

Nerve Injury-Induced Protein 1

NLRC4

NLR Family CARD Domain Containing 4

NLRP12

NLR Family Pyrin Domain Containing 12

NLRP3

NOD-, LRR- and Pyrin Domain-Containing Protein 3

PAMPs

Pathogen-Associated Molecular Patterns

PCD

Programmed Cell Death

PGAM5

Phosphoglycerate Mutase Family Member 5

PRRs

Pattern Recognition Receptors

PSMD14

Proteasome 26S Subunit, Non-ATPase 14

PYD-CARD

Pyrin Domain – caspase Activation and Recruitment Domain

RCD

Regulated Cell Death

RHIM

RIP Homotypic Interaction Motif

RIPK1

Receptor-Interacting Protein Kinase 1

RIPK3

Receptor-Interacting Protein Kinase 3

ROS

Reactive Oxygen Species

SAH

Subarachnoid Hemorrhage

SCI

Spinal Cord Injury

STAT1

Signal Transducer and Activator of Transcription 1

TAK1

TGF-β-Activated Kinase 1

TBI

Traumatic Brain Injury

TUDCA

Tauroursodeoxycholic Acid

ZBP1

Z-DNA Binding Protein 1

The role of PANoptosis regulatory networks in acute neurological injury

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