Glutathione Peroxidase 4 (gpx4) In Subclinical Hypothyroidism: LinkingOxidative Stress And Thyroid Dysfunction

Abstract

Subclinical hypothyroidism (SCH) is defined by elevated thyroid-stimulating hormone (TSH) levels with normal circulating thyroid hormones and is associated with increased cardiovascular risk and metabolic disturbances. A pivotal, yet underexplored, aspect of SCH pathophysiology is oxidative stress (OS):- an imbalance between reactive oxygen species (ROS) production and antioxidant defenses. The thyroid gland is particularly susceptible to oxidative damage due to its high oxidative environment needed for hormone synthesis. Glutathione peroxidase 4 (GPX4), a selenium-dependent selenoenzyme, is critical for neutralizing lipid peroxides and protecting thyrocytes from ROS-induced injury and ferroptotic cell death. Impaired GPX4 activity, often linked to selenium deficiency or persistent OS, may exacerbate thyroid dysfunction, suggesting a mechanistic link between redox imbalance and the evolution of SCH. While animal studies and indirect clinical evidence highlight reduced GPX4 expression and altered selenium status in thyroid disorders, direct clinical correlations in SCH remain limited. Elucidating GPX4’s role in thyroid redox biology could enhance early diagnosis, enable risk stratification, and inform personalized interventions, such as targeted antioxidant or micronutrient supplementation. This review underscores the need for integrative clinical studies to clarify GPX4’s functional significance in SCH and explores its therapeutic potential in mitigating progression to overt hypothyroidism.