Role of xCT-mediated amino acid transport in cancer progression

Ferroptosis is an iron-dependent form of cell death triggered by the accumulation of lipid peroxides.Highly proliferative cancer cells evade ferroptosis by enhancing antioxidant systems.The cystine-glutamate antiporter xCT (SLC7A11) plays a key role in ferroptosis resistance by promoting cystine uptake and glutathione (GSH) synthesis, thereby increasing oxidative stress tolerance.In particular, cancer stem-like cells expressing the CD44 variant (CD44v) stabilize xCT at the cell surface, leading to elevated intracellular GSH levels and enhanced ferroptosis resistance.Additionally, aldehyde dehydrogenases (ALDHs) detoxify lipid peroxidation byproducts, such as 4-hydroxynonenal (4-HNE) , further contributing to ferroptosis evasion.We previously reported that the xCT inhibitor sulfasalazine (SSZ) induces ferroptosis in cancer cells; however, some cancer cells exhibit resistance despite GSH depletion.Through synthetic lethal screening, we identified ALDH inhibitors, including dyclonine (DYC) and oxyfedrine (OXY) , as potent sensitizers to SSZ.These compounds covalently bind to the catalytic site of ALDH, suppressing its activity and leading to the accumulation of toxic lipid peroxides, thereby enhancing ferroptosis induction.In tumor-bearing mouse models, the combination of SSZ with DYC or OXY exhibited strong antitumor effects with minimal systemic toxicity, highlighting its potential as a safe and effective therapeutic strategy.In this review, we summarize recent advances in ferroptosis-based cancer therapy and introduce our approach to developing a novel therapeutic strategy targeting xCT and ALDH.We discuss the potential clinical application of this strategy, including an ongoing physician-led clinical trial, and its implications for overcoming ferroptosis resistance in cancer.