Xiaoyu Zhang, Liming Cheng, Jiahui Xie, Xuejuan Ma, Wenting Gui, Jiaxiang Chen, Kai Liu, Runwei Ma
Fuwai Yunnan Hospital, Kunming Children’s Hospital, Chinese Academy of Medical Sciences and Affiliated Cardiovascular Hospital of Kunming Medical University.
China
Frontiers in Physiology
Front Physiol 2025; 14:
DOI: 10.3389/fphys.2025.1673181
Abstract
Background: Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling and mitochondrial dysfunction. Recent studies have implicated impaired mitophagy in the pathogenesis of PAH; however, the underlying mechanisms and associated biomarkers remain insufficiently defined. This study used an integrative approach, incorporating bulk transcriptomic profiling, single-cell RNA sequencing (scRNA-seq), machine learning algorithms, and experimental validation to explore the relationship between mitophagy and PAH.
Methods: Differentially expressed genes were extracted from publicly available microarray datasets and intersected with mitophagy-related genes curated from the MitoCarta 3.0 database. Weighted gene co-expression network analysis, along with five distinct machine learning models, identified five candidate mitophagy-associated biomarkers: RRAS, BECN1, MFN1, HIF1A, and TAX1BP1. These genes demonstrated high diagnostic performance (area under the curve >0.9) across both training and validation cohorts. Immune cell deconvolution analysis indicated a marked increase in M1 macrophage infiltration in lung tissue from individuals with PAH. The scRNA-seq further localized the expression of these biomarkers predominantly to monocyte/macrophage populations and indicated distinct pseudotemporal expression trajectories during macrophage differentiation. Expression and co-localization of the identified biomarkers with autophagy and inflammation markers were subsequently validated using quantitative PCR, western blotting, and immunofluorescence in a monocrotaline-induced PAH rat model.
Results and conclusion: The findings underscore the involvement of mitophagy in the pathobiology of PAH and identify five macrophage-associated biomarkers with strong diagnostic potential. These results may inform future strategies aimed at early detection and targeted therapeutic interventions in PAH.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Potential Biomarkers Associated with Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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