Chaohong Chen, Zaoye Xie, DangAo, Yinhui Chen, Ling Liu, Chengyan Li
Affiliated Hospital of Guangdong Medical University.
China
Scientific Reports
Sci Rep 2025; 15:
DOI: 10.1038/s41598-025-07068-5
Abstract
Persistent pulmonary hypertension of the newborn (PPHN) represents a life-threatening cardiopulmonary condition characterized by hypoxia-driven pulmonary vascular remodeling. While transcription factor EB (TFEB), a master regulator of cellular adaptation to hypoxia, has been implicated in vascular pathologies, its mechanistic role in PPHN remains undefined. This study elucidates the molecular interplay of TFEB in hypoxia-induced PPHN pathogenesis. Fetal rat models of hypoxia-induced PPHN, including untreated hypoxic models and hypoxic models treated with the TFEB inhibitor Eltrombopag (EO), as well as a hypoxia-induced human pulmonary artery endothelial cell (HPAEC) model, were established. Multimodal assessments, including histopathology, qRT-PCR, JC-1 staining, immunofluorescence, flow cytometry, and Western blotting, were employed to evaluate the effects of TFEB on mitophagy and NLRP3 inflammasome. In the hypoxia group, significant thickening of the pulmonary arterioles and right ventricular wall was observed. Immunostaining revealed a significant increase in the relative staining density of TFEB-positive, NLRP3-positive, and LC3-positive cells, alongside elevated expression of mitophagy-proteins and NLRP3 inflammasome-related proteins. TFEB inhibition downregulated the expression of PINK1, TOMM20, COX IV, P62, and LC3II/I ratio, impairing mitophagy, while upregulating eNOS, NLRP3, and GSDMD, thereby enhancing NLRP3 activation and pyroptosis. In the EO group, fetal rats exhibited more pronounced pulmonary arteriole thickening, intensified fluorescence signals for NLRP3, caspase-1, and GSDMD, reduced mitophagy-related protein expression, and further elevated NLRP3 inflammasome-related protein and GSDMD expression. TFEB exerts a protective effect in PPHN by inhibiting NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy, highlighting TFEB’s potential as a therapeutic target for hypoxia-induced PPHN.
Category
Class I. Persistent Pulmonary Hypertension of the Newborn
Genetic Factors Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes