Ferroptosis is an iron-dependent, non-apoptotic form of cell death regulated by a complex redox system, involving both pro-oxidative and antioxidant proteins. These proteins are regulated through various post-translational modifications (PTMs), including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification. These modifications influence protein stability, activity, localization, and interactions, affecting iron accumulation and lipid peroxidation. In mammalian cells, ferroptosis is primarily regulated by the ubiquitin-proteasome system (UPS) and autophagy. This review summarizes recent advances in PTMs and protein degradation related to ferroptosis, discussing strategies to modulate ferroptosis through these systems for potential therapeutic applications in cancer and non-neoplastic diseases. Ferroptosis is characterized by oxidative cell death due to the peroxidation of polyunsaturated fatty acids (PUFAs) in phospholipids. Key mechanisms include iron accumulation, lipid peroxidation, and antioxidant defense. Iron accumulation can be regulated through various steps, including iron uptake, storage, and efflux. Lipid peroxidation is a critical factor in ferroptosis, involving enzymes like ACSL4, LPCAT3, and ALOXs. Antioxidant defense systems, such as the GPX4-GSH system and the CoQ system, play essential roles in protecting against ferroptosis. PTMs, including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification, regulate ferroptosis by modulating protein function and stability. These modifications influence iron metabolism, lipid peroxidation, and antioxidant defense. Protein degradation via the UPS and autophagy is crucial for regulating ferroptosis, with specific E3 ubiquitin ligases and deubiquitinating enzymes playing key roles in the degradation of proteins involved in ferroptosis. The regulation of ferroptosis involves complex interactions between PTMs and protein degradation mechanisms, offering potential therapeutic targets for modulating ferroptosis in various diseases. Understanding these mechanisms is essential for developing targeted therapies for cancer and other diseases associated with ferroptosis.Ferroptosis is an iron-dependent, non-apoptotic form of cell death regulated by a complex redox system, involving both pro-oxidative and antioxidant proteins. These proteins are regulated through various post-translational modifications (PTMs), including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification. These modifications influence protein stability, activity, localization, and interactions, affecting iron accumulation and lipid peroxidation. In mammalian cells, ferroptosis is primarily regulated by the ubiquitin-proteasome system (UPS) and autophagy. This review summarizes recent advances in PTMs and protein degradation related to ferroptosis, discussing strategies to modulate ferroptosis through these systems for potential therapeutic applications in cancer and non-neoplastic diseases. Ferroptosis is characterized by oxidative cell death due to the peroxidation of polyunsaturated fatty acids (PUFAs) in phospholipids. Key mechanisms include iron accumulation, lipid peroxidation, and antioxidant defense. Iron accumulation can be regulated through various steps, including iron uptake, storage, and efflux. Lipid peroxidation is a critical factor in ferroptosis, involving enzymes like ACSL4, LPCAT3, and ALOXs. Antioxidant defense systems, such as the GPX4-GSH system and the CoQ system, play essential roles in protecting against ferroptosis. PTMs, including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification, regulate ferroptosis by modulating protein function and stability. These modifications influence iron metabolism, lipid peroxidation, and antioxidant defense. Protein degradation via the UPS and autophagy is crucial for regulating ferroptosis, with specific E3 ubiquitin ligases and deubiquitinating enzymes playing key roles in the degradation of proteins involved in ferroptosis. The regulation of ferroptosis involves complex interactions between PTMs and protein degradation mechanisms, offering potential therapeutic targets for modulating ferroptosis in various diseases. Understanding these mechanisms is essential for developing targeted therapies for cancer and other diseases associated with ferroptosis.