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Review Open Access

PANoptosis: A novel therapeutic target in kidney disease (Review)

  • Authors:
    • Lianyan Jiang
    • Liangbin Zhao
    • Yu Liu
    • Zhongmei Fu
    • Mengzhu Wu
    • Zengyi Mou
    • Mingquan Li
  • View Affiliations / Copyright

    Affiliations: School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610032, P.R. China, Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China, Department of Nephrology, The Chinese University of Hong Kong, Shenzhen Medical Centre, Shenzhen, Guangdong 518100, P.R. China
    Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 207
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    Published online on: September 26, 2025
       https://doi.org/10.3892/ijmm.2025.5648
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Abstract

The global prevalence of kidney diseases continues to rise annually, posing a serious public health challenge, and notably contributing to morbidity and mortality rates worldwide. In affected individuals, kidney function progressively declines, ultimately resulting in renal failure. Therefore, elucidating the pathophysiological mechanisms underlying kidney diseases and identifying novel therapeutic targets is of paramount importance. Among these, the regulation of cell death pathways has emerged as a pivotal factor in disease progression. PANoptosis, a recently characterized form of programmed cell death, is activated by diverse stimuli, and involves the integrated activation of pyroptosis, apoptosis and necroptosis, coordinated through the PANoptosome complex. Increasing evidence has suggested that PANoptosis serves an important role in the development of kidney diseases, and further investigation into its regulatory mechanisms may provide valuable insights into disease modulation. The present review summarizes current knowledge regarding the mechanisms of PANoptosis and its involvement in various kidney diseases, offering perspectives for future diagnostic and therapeutic strategies.
View Figures

Figure 1

Timeline of the discovery of
apoptosis, necroptosis, pyroptosis and PANoptosis. In 2019,
PANoptosis was first named, and four types of PANoptosomes have
since been characterized. Created with MedPeer (medpeer.cn).
NLRP12, Nod-like receptor pyrin domain-containing protein 12;
RIPK1, receptor-interacting protein kinase 1; ZBP1, Z-DNA binding
protein 1.

Figure 2

Mechanisms of apoptosis, necroptosis
and pyroptosis. (A) Apoptosis depends on the involvement and
regulation of caspases, and is divided into intrinsic (dependent on
caspase-9) and extrinsic (dependent on caspase-8/10) pathways,
which respectively cleave downstream factors dependent on
caspase-3/6/7 to perform apoptosis. (B) RIPK1 recruits and
phosphorylates RIPK3 in necroptosis, further activating MLKL. MLKL
has pore-forming activities, leading to necroptosis. (C) Pyroptosis
is divided into classical (dependent on caspase-1) and
non-classical (dependent on caspase-4/5/11) pathways, which rely on
the cleavage of the executive protein GSDMD, forming N-terminal
GSDMD fragments that form pores in the cell membrane, inducing the
release of inflammatory exudate and driving pyroptosis. The three
modes of cell death are not isolated, but interact with each other,
for example, caspase-8 is involved in regulating all three cell
death modes simultaneously. Created with MedPeer (medpeer.cn).
APAF-1, apoptotic protease-activating factor 1; ASC,
apoptosis-related speck-like protein; Cyt c, cytochrome c;
DAMPs, damage-associated molecular patterns; DISC, death-inducing
signaling complex; FADD, Fas-associated death domain protein;
GSDMD, gasdermin D; LPS, lipopolysaccharide; MLKL, mixed-lineage
kinase domain-like protein; MOMP, mitochondrial outer membrane
permeabilization; NLRP3, Nod-like receptor pyrin domain-containing
protein 3; PAMPs, pathogen-associated molecular patterns; RIPK,
receptor-interacting protein kinase; ROS, reactive oxygen species;
TNF, tumor necrosis factor; TNFR, TNF receptor; TRADD,
TNFR-associated death domain protein; TRAIL, TNF-related
apoptosis-inducing ligand; TRAILR, TRAIL receptor.

Figure 3

Molecular compositions and mechanisms
of the PANoptosome complexes. (A) ZBP1-PANoptosome consists of
RIPK3, caspase-8, caspase-6, caspase-1, RIPK1, ZBP1, ASC and NLRP3.
(B) AIM2-PANoptosome is assembled by combining molecules such as
AIM2, ZBP1, pyrin, ASC, caspase-8, caspase-1, RIPK3, RIPK1, NLRP3
and FADD. (C) RIPK1-PANoptosome contains molecules such as
caspase-8, caspase-1, FADD, NLRP3, ASC, RIPK1 and RIPK3. (D)
NLRP12-PANoptosome consists of NLRP12, caspase-1, caspase-8, RIPK3,
NLRP3 and ASC. The four PANoptosomes all contain key factors for
three cell death modes, caspase-3/7, MLKL and GSDMD, which induce
apoptosis, necroptosis and pyroptosis, respectively. Created with
MedPeer (medpeer. cn). AKI, acute kidney injury; ASC,
apoptosis-related speck-like protein; CKD, chronic kidney disease;
DAMPs, damage-associated molecular patterns; FADD, Fas-associated
death domain protein; GSDMD, gasdermin D; HSV1, herpes simplex
virus 1; IAV, influenza A virus; MLKL, mixed-lineage kinase
domain-like protein; NLRP, Nod-like receptor family pyrin domain
containing; PAMPs, pathogen-associated molecular patterns; RCC,
renal cell carcinoma; RIPK, receptor-interacting protein kinase;
TAK1, transforming growth factor-β-activated kinase 1; TLR,
Toll-like receptor; ZBP1, Z-DNA binding protein 1.
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Copy and paste a formatted citation
Spandidos Publications style
Jiang L, Zhao L, Liu Y, Fu Z, Wu M, Mou Z and Li M: PANoptosis: A novel therapeutic target in kidney disease (Review). Int J Mol Med 56: 207, 2025.
APA
Jiang, L., Zhao, L., Liu, Y., Fu, Z., Wu, M., Mou, Z., & Li, M. (2025). PANoptosis: A novel therapeutic target in kidney disease (Review). International Journal of Molecular Medicine, 56, 207. https://doi.org/10.3892/ijmm.2025.5648
MLA
Jiang, L., Zhao, L., Liu, Y., Fu, Z., Wu, M., Mou, Z., Li, M."PANoptosis: A novel therapeutic target in kidney disease (Review)". International Journal of Molecular Medicine 56.6 (2025): 207.
Chicago
Jiang, L., Zhao, L., Liu, Y., Fu, Z., Wu, M., Mou, Z., Li, M."PANoptosis: A novel therapeutic target in kidney disease (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 207. https://doi.org/10.3892/ijmm.2025.5648
Copy and paste a formatted citation
x
Spandidos Publications style
Jiang L, Zhao L, Liu Y, Fu Z, Wu M, Mou Z and Li M: PANoptosis: A novel therapeutic target in kidney disease (Review). Int J Mol Med 56: 207, 2025.
APA
Jiang, L., Zhao, L., Liu, Y., Fu, Z., Wu, M., Mou, Z., & Li, M. (2025). PANoptosis: A novel therapeutic target in kidney disease (Review). International Journal of Molecular Medicine, 56, 207. https://doi.org/10.3892/ijmm.2025.5648
MLA
Jiang, L., Zhao, L., Liu, Y., Fu, Z., Wu, M., Mou, Z., Li, M."PANoptosis: A novel therapeutic target in kidney disease (Review)". International Journal of Molecular Medicine 56.6 (2025): 207.
Chicago
Jiang, L., Zhao, L., Liu, Y., Fu, Z., Wu, M., Mou, Z., Li, M."PANoptosis: A novel therapeutic target in kidney disease (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 207. https://doi.org/10.3892/ijmm.2025.5648
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