GPX4: A Key Regulator of Mitochondrial Function and Glycolysis in Pulmonary Artery Smooth Muscle Cells

ABSTRACT: Pulmonary arterial hypertension is a progressive cardiovascular disease characterized by elevated pulmonary arterial pressure and vascular remodeling. However, the underlying mechanisms remain unclear. This study reveals a novel mechanism by which oxidative stress reduced glutathione peroxidase 4 (GPX4) expression in both rat and human pulmonary arterial smooth muscle cells (PASMCs), establishing a reciprocal regulatory relationship between GPX4 and reactive oxygen species. GPX4 deficiency in PASMCs exacerbated inflammation, evidenced by increased IL-6 and TNF-α, and promoted extracellular matrix remodeling, indicated by elevated fibronectin and collagen II. Moreover, GPX4 inhibition disrupted mitochondrial function by downregulating key mitochondrial regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) and mitochondrial transcription factor A. Simultaneously, it promoted glycolysis, leading to increased lactate production through the upregulation of lactate dehydrogenase A and hexokinase 2. These effects were associated with the long noncoding RNA TUG1, which appeared to modulate GPX4 stability. Collectively, our findings identify GPX4 as a critical regulator of inflammation, extracellular matrix remodeling, and metabolic homeostasis in PASMCs, providing new insights into the molecular mechanisms underlying pulmonary arterial hypertension and identify potential therapeutic targets.