Deubiquitinating enzymes-mediated post-translational modifications of ferroptosis regulates cancer drug resistance

Cancer drug resistance remains a formidable challenge in oncology, severely limiting the efficacy of conventional chemotherapy, targeted therapy, and immunotherapy. Ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation, has emerged as a critical tumor suppression mechanism and a promising avenue to overcome drug resistance. Many resistant cancer cells exhibit a marked dependency on the ferroptosis defense pathway, making them vulnerable to ferroptosis induction. Central to the regulation of ferroptosis are a suite of key positive and negative regulators. Their protein stability, activity, and subcellular localization are intricately controlled by post-translational modifications (PTMs). Among these, deubiquitinating enzymes (DUBs) have surfaced as a paramount regulatory mechanism. This review systematically elaborates on how DUBs orchestrates the fate of core ferroptosis regulators by targeting them for proteasomal or lysosomal degradation, or by modulating their activity. We comprehensively summarize the burgeoning evidence of how ubiquitin-mediated modifications of the ferroptosis pathway directly contribute to the development of resistance against various anti-cancer drugs. Furthermore, we discuss the profound therapeutic implications of targeting the ubiquitin-ferroptosis axis, highlighting strategies to leverage ubiquitination pathways to re-sensitize resistant tumors to treatment. Ultimately, a deeper understanding of ubiquitination in ferroptosis regulation not only elucidates a fundamental mechanism of drug resistance but also paves the way for novel therapeutic interventions designed to eradicate treatment-resistant cancers by triggering ferroptosis.