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

Pulmonary arterial hypertension (PAH) 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 (ROS). GPX4 deficiency in PASMCs exacerbated inflammation, evidenced by increased IL-6 and TNF-α, and promoted extracellular matrix (ECM) 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 (TFAM). Simultaneously, it promoted glycolysis, leading to increased lactate production through the upregulation of lactate dehydrogenase A (LDHA) and hexokinase 2 (HK2). These effects were associated with the long non-coding RNA TUG1, which appeared to modulate GPX4 stability. Collectively, our findings identify GPX4 as a critical regulator of inflammation, ECM remodeling and metabolic homeostasis in PASMCs, providing new insights into the molecular mechanisms underlying PAH and identify potential therapeutic targets.