Effects of MTOR and NRF2 signaling on ferrptosis in hyperthyroidism

The thyroid is an endocrine gland responsible for the production of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), which act on all cells in the body to regulate development, growth, and metabolism. Hyperthyroidism is a pathological syndrome where the tissue is exposed to excessive circulating thyroid hormones. Due to hyperthyroidism, mitochondrial oxidative metabolism accelerates, increasing reactive oxygen species (ROS). The increase in ROS can cause oxidative stress. Nuclear factor erythroid 2-related factor 2 (NRF2) is the primary and most important transcriptional activator that is redox-sensitive and activates to initiate cell-protective reactions against oxidative stress, being considered the main regulator of the antioxidant response. Ferroptosis is a type of regulated cell death characterized by intracellular lipid and ROS accumulation when the antioxidant capacity of cells decreases, and it is controlled by iron chelators and lipophilic antioxidants. When cells are subjected to ferroptosis, both the expression and activity of GPX4 in the antioxidant system will decrease. NRF2 is a critical mitigator of both lipid peroxidation and ferroptosis. Among the regulators of ferroptosis is the mammalian target of rapamycin complex 1 (MTORC1), an evolutionarily conserved serine-threonine kinase that modulates cell cycle progression and growth by sensing changes in energy balance, growth factors, nutrients, and oxygen. The mammalian target of rapamycin (MTOR) is a downstream effector of the phosphatidylinositol-3 kinase (PI3K) /Akt pathway, which also regulates iodide uptake in thyroid cells. Our ongoing thesis project aims to investigate the ferroptosis pathway in patients with hyperthyroidism. Our study comprises a total of two groups: 90 patients with hyperthyroidism and 90 individuals in the control group, making a total of 180 participants. The biochemical parameters used in our study include long-chain fatty acid-CoA ligase 4 (ACSL4), glutathione (GSH), malondialdehyde (MDA), MTOR, NRF2, total antioxidant status (TAS), and total oxidant status (TOS), all of which were analyzed using the Enzyme-Linked Immunosorbent Assay (ELISA) method. Based on the obtained data, it was observed that there was an increase in the biochemical parameters ACSL4, MDA, MTOR, and TOS in the serum of patients with hyperthyroidism compared to the serum of individuals in the control group. On the other hand, it was found that the biochemical parameters GSH, NRF2, and TAS decreased compared to the control group. According to our results, it was determined that the ferroptosis signaling pathway is induced based on the serum analyses conducted on individuals with hyperthyroidism. This study suggests that detailed studies on the inhibition of the MTOR pathway and the induction of the NRF2 pathway could contribute to mitigating the damage caused by ferroptosis under hyperthyroid conditions.