Cysteine metabolism at the crossroads of ferroptosis and cancer therapy.

Cysteine metabolism plays a pivotal role in ferroptosis regulation by modulating antioxidant defense, lipid peroxidation, and iron homeostasis. Cancer cells exploit cysteine availability to evade ferroptotic cell death, contributing to tumor progression and therapy resistance. Despite growing interest in ferroptosis as a therapeutic vulnerability, a comprehensive understanding of cysteine metabolism in this process remains essential. This review explores key sources of intracellular cysteine, its roles in ferroptosis suppression, and therapeutic strategies targeting cysteine metabolism in cancer. We discuss systemic cysteine depletion, xCT inhibition, suppression of H2S biosynthesis, and GPX4-targeted therapies, along with promising drug combinations. While preclinical studies highlight the efficacy of these approaches, in vivo validation and clinical translation remain limited. Advancing cysteine-targeting therapies require further mechanistic insights, biomarker identification, and optimized delivery strategies. A deeper understanding of cysteine metabolism may pave the way for ferroptosis-based cancer treatments with improved precision and efficacy.