Identification and Validation of TFF3 as a Diagnostic Biomarker and Therapeutic Agent for Bronchopulmonary Dysplasia.

Background: Bronchopulmonary dysplasia (BPD) is a common and severe complication in preterm infants, driven by oxidative stress, inflammation, and disrupted alveolar development. Despite advancements in neonatal care, current treatments remain supportive, with limited options targeting the underlying mechanisms of BPD pathogenesis. Emerging evidence suggests that modulating cell death pathways, including apoptosis and pyroptosis, may provide therapeutic benefits. This study aims to investigate the role of TFF3 as a diagnostic biomarker and therapeutic agent for BPD, focusing on its potential to regulate cell death and promote alveolar repair.

Methods: Tracheal aspirate samples from BPD and control groups were analyzed using the GSE156028 data set to identify differentially expressed genes (DEGs). Oxidative stress (OS)-related DEGs were prioritized through protein-protein interaction (PPI) network analysis and machine learning algorithms (XGBoost and random forest). Experimental validation was conducted in a hyperoxia-induced BPD rat model and RLE-6TN cells to evaluate TFF3's effects on alveolar development, inflammation, apoptosis, and pyroptosis through histological, immunohistochemical, and molecular assays.

Results: TFF3 was identified as a top-ranking biomarker for BPD, with robust diagnostic performance (AUC = 0.709). Hyperoxia-induced BPD rats exhibited reduced TFF3 expression, severe alveolar simplification, and elevated apoptotic and pyroptotic markers. TFF3 treatment significantly improved alveolar structure, reduced mean linear intercept (MLI), and partially restored pulmonary vascular density. In vitro, TFF3 enhanced cell viability, suppressed cleaved caspase-3 and NLRP3 expression, and decreased IL-1β and IL-18 secretion. These results demonstrate that TFF3 mitigates hyperoxia-induced inflammation, apoptosis, and pyroptosis while promoting alveolar and vascular repair.

Conclusions: TFF3 serves as a promising biomarker and Therapeutic agent for BPD. By regulating multiple pathological pathways, TFF3 alleviates hyperoxia-induced lung injury and restores alveolar development. These findings provide a foundation for future clinical studies aimed at optimizing TFF3-based therapies for preterm infants with BPD.