PP4 deficiency drives airway epithelial senescence via the PERK-eIF2α-ATF4-p21 axis in severe asthma

Cellular senescence, defined by irreversible cell cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical driver of airway inflammation and hyperresponsiveness in asthma. Despite well-established associations between senescence, aging, and chronic disease, its precise mechanistic role in asthma pathogenesis remains poorly understood. Protein phosphatase 4 (PP4), a serine/threonine phosphatase with broad physiological functions, is significantly downregulated in airway epithelial cells derived from patients with severe asthma, suggesting a potential regulatory role in disease progression.

Bulk RNA sequencing (RNA-seq) was performed to assess transcriptomic changes in PP4-deficient airway epithelial cells. Mechanistic studies examined downstream signaling through PERK phosphorylation, p21-dependent senescence pathways, mitochondrial function, and calcium dynamics. A house dust mite (HDM)-induced murine asthma model was employed to evaluate the therapeutic efficacy of the PERK inhibitor GSK2656157 in vivo. Ex vivo validation was conducted using air-liquid interface (ALI)-cultured human bronchial epithelial cells (HBECs) obtained from patients with severe asthma.

RNA-seq analysis revealed that PP4 deficiency significantly upregulates endoplasmic reticulum (ER) stress-related gene expression in airway epithelial cells. Mechanistically, PP4 loss enhanced PERK phosphorylation, activating the PERK-eIF2α-ATF4-p21 signaling axis, which in turn triggered p21-dependent cellular senescence, mitochondrial dysfunction, and intracellular calcium influx. In the HDM-induced asthma model, pharmacological inhibition of PERK with GSK2656157 attenuated airway epithelial senescence and significantly reduced systemic levels of IgE, IL-5, and IL-13. Consistently, GSK2656157 treatment effectively suppressed p21-mediated senescence and SASP in ALI-cultured HBECs from severe asthmatic donors.

These findings demonstrate that PP4 governs airway epithelial senescence through the PERK-eIF2α-ATF4-p21 signaling axis, mechanistically linking ER stress to SASP-driven airway inflammation in asthma. Targeting PP4-related pathways represents a promising therapeutic strategy for managing senescence-associated pathology in severe asthma.