GSK'872 mitigates ischemia-reperfusion injury in rat lung transplants by regulating PANoptosis and inflammation in cell type specific manner.

Authors

Jinsheng Li, Xingjie Ma, Jinghao Huang, Yifan Yu, Zhiling Lou, Fuxiang Liang, Xiaolong Hu, Qiuyu Fang, Yongchao Wang, Mingyao Liu, Yunbi Lu, Ming Wu

Published in

Cell communication and signaling : CCS. Jul 04, 2026. Epub Jul 04, 2026.

Abstract

Ischemia-reperfusion injury (IRI) greatly impairs lung transplantation (LTx) outcomes, with no effective treatments. Although existing studies have confirmed that cell death and inflammation responses are critical in LTx-IRI, the specific cell death profiles of various parenchymal and inflammatory cells remain to be elucidated.
Using human single-cell RNA sequencing data from LTx-IRI, we identified activation of genes related to cell death and inflammation pathways. We examined the effects and mechanisms of a RIPK3 inhibitor, GSK'872, on IRI with a rat LTx model.
GSK'872, added to lung preservation solution, injected to recipients, or in combination, reduced alveolar hemorrhage, perivascular edema, neutrophil infiltration and suppressed necroptosis, pyroptosis, and inflammation in lung tissues. GSK'872 decreased MLKL phosphorylation in type 2 alveolar epithelial cells and macrophages, and RIPK3 phosphorylation in neutrophils. GSK'872 induced apoptosis in RAW264.7 macrophages via RIPK1 and caspase 3 cleavage in a cold ischemia/warm reperfusion (CI/R) cell culture model. GSK'872 inhibited lipopolysaccharide (LPS)-stimulated neutrophil extracellular traps (NETs) formation with suppressed necroptosis and pyroptosis. GSK'872 did not rescue BEAS-2B lung epithelial cells from CI/R-induced cell death. However, conditioned medium from GSK'872-treated macrophages (after CI/R) or neutrophils (challenged by LPS) reduced CI/R-induced decrease in BEAS-2B cell viability.
GSK'872 alleviates LTx-IRI by inhibiting necroptosis and pyroptosis in macrophages and neutrophils directly, and protects lung epithelial cells via blocking soluble mediators indirectly. Administration of GSK'872 to lung preservation solution and/or injection to recipients may be new treatment options for IRI in LTx.

PMID:
42401940
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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