Ferroptosis, an iron-dependent form of programmed cell death, was first defined in 2012. It is triggered by the excessive accumulation of lipid peroxides and disruption of oxidative homeostasis, and is characterized by mechanisms and morphological features distinct from those of apoptosis, necrosis, and autophagy. Glutathione peroxidase 4 (GPX4), the fourth member of the GPX family, is the core regulator of ferroptosis. It maintains redox homeostasis and prevents ferroptosis by relying on glutathione to catalyze the reduction of lipid hydroperoxides to their corresponding lipid alcohols. GPX4 dysfunction is linked to various diseases, and is involved in cancer drug resistance and neurodegenerative disorders. Post-translational modifications of GPX4 ( such as ubiquitination and phosphorylation) are crucial in regulating ferroptosis, and the development of GPX4-targeted inhibitors has emerged as a novel strategy in cancer therapy. This review systematically synthesizes the regulatory mechanisms governing GPX4 modifications and the development of GPX4 inhibitors, and provides possible directions for future research.