Ubiquitin regulatory code: unraveling tumor cell ferroptosis

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, characterized by the inhibition of glutathione peroxidase 4 (GPX4), glutathione (GSH) depletion, and peroxidation of polyunsaturated fatty acids (PUFAs). Due to metabolic reprogramming and impaired antioxidant defenses, tumor cells exhibit heightened sensitivity to ferroptosis, positioning it as a promising therapeutic target for cancer. Within the cellular protein regulatory network, post-translational modifications (PTMs) -particularly ubiquitination and ubiquitin-like modifications (Ubls, including SUMOylation, NEDDylation, UFMylation, and ATG8ylation) -serve as molecular switches by modulating the stability of key proteins such as GPX4 and SLC7A11. This review systematically dissects how E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) orchestrate redox homeostasis and iron metabolism, through site-specific ubiquitination of critical proteins. Furthermore, we highlight the development of small-molecule inhibitors targeting these modifications, emphasizing their potential to disrupt ferroptosis resistance pathways. By integrating mechanistic insights with therapeutic applications, this study not only elucidates the dynamic complexity of ubiquitin-mediated regulatory networks but also proposes innovative strategies leveraging Ub/Ubl modifications for targeted cancer therapy. These findings provide a foundational theoretical framework and actionable research directions for advancing precision medicine in oncology.