Loss of PP4 drives airway senescence through endoplasmic reticulum stress
Inhibiting the PERK pathway lowered cellular senescence and inflammatory markers in mouse models and cultured human airway cells.
Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Huang YT et al. · Paper published 27 Sep 2026
In mice and cultured human airway cells, researchers investigated how the loss of protein phosphatase 4 (PP4) promotes lung pathology. PP4 levels are significantly decreased in airway epithelial cells from patients with severe asthma. Bulk RNA sequencing showed that PP4 deficiency boosted endoplasmic reticulum stress genes. Mechanistically, PP4 loss promoted PERK phosphorylation, activating a PERK-eIF2α-ATF4-p21 cascade that caused p21-dependent cellular senescence, mitochondrial dysfunction, and calcium influx. Pharmacological inhibition of PERK using GSK2656157 attenuated airway epithelial senescence and lowered systemic IgE, IL-5, and IL-13 in a house dust mite-induced mouse model. The same inhibitor also suppressed p21-mediated senescence and the senescence-associated secretory phenotype in cultured human bronchial epithelial cells from severe asthma donors.
Why it matters
The study directly links endoplasmic reticulum stress to cellular senescence and secretory phenotypes in respiratory tissues. Mapping this signaling axis reveals potential targets for managing senescence-driven chronic inflammatory diseases.
Caveats
The findings rely on mouse models and ex vivo cell cultures rather than in vivo clinical trials. Further research is necessary to evaluate the safety and therapeutic potential of PERK inhibitors in humans.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
PP4 deficiency drives airway epithelial senescence via the PERK-eIF2α-ATF4-p21 axis in severe asthma
Huang YT, Chen CY, Weng CM et al.
Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 27 Sep 2026 · Peer-reviewed
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