Ferroptosis is an iron-dependent form of cell death characterized by accumulation of lipid peroxidation products and lethal reactive oxygen species leading to plasma membrane disruption and necrotic-like cell death. This process is triggered by the inactivation of GPX4, a key antioxidant enzyme which prevents toxic lipid peroxide buildup. Nrf2, another regulator, protects cells from oxidative stress by regulating the endogenous antioxidant response. Upon activation, Nrf2 enhances the expression of GPX4, SLC7A11, and HMOX1, maintaining redox balance and controlling intracellular iron levels. In addition, TIGAR, protects cells from ferroptosis by promoting NADPH generation and limiting ROS accumulation. The neurotrophic factor, GDNF, is a potent survival and differentiation factor for motor neurons. To analyze its potential neuroprotective action against ferroptosis, motor neuron-derived cell line was cultured with GDNF plus its receptor GFRα1 for 1, 2, 4, 6 and 8h, and untreated cells served as controls. The aforementioned genes expression was quantified by PCR. GPX4 and Nrf2 showed a significant increase throughout incubation time, specifically starting after the first hour of treatment for Nrf2 and after 4 hours for GPX4. Overall, all genes increased their expression as incubation progressed. These results suggest that GDNF could exert a protective role in motor neuron-derived cells by inducing the expression of genes that negatively regulate ferroptosis.