Targeting 15-PGDH/15-oxoETE to mitigate inflammation and senescence in asthma

Asthma is a chronic airway disease characterized by airway inflammation and remodeling. While 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and its metabolic product 15-oxo-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-oxoETE), are known to participate in inflammatory regulation in several diseases its specific role in asthma remains unclear. In this study, we revealed a significant and concurrent upregulation of both 15-PGDH and 15-oxoETE in the lung tissues of asthmatic mice. In vitro, TNF-α stimulation increased 15-PGDH expression in bronchial epithelial cells. Mechanistically, 15-PGDH/15-oxoETE drove epithelial cell senescence and pro-inflammatory cytokine release, which was mediated by 15-oxoETE directly binding to and stabilizing IGFBP5. Notably, SW033291, a selective 15-PGDH inhibitor, prevented and alleviated airway inflammation and remodeling in acute asthmatic mice, while also exerting significant therapeutic effects in chronic asthma models. In summary, 15-PGDH/15-oxoETE acts as a critical driver of airway inflammation and epithelial senescence in asthma, and targeting this pathway may provide a promising therapeutic strategy.