Role of the sulfur-containing amino acid-ROS axis in cancer chemotherapeutic drug resistance

Chemotherapeutic drug resistance remains a major barrier to effective cancer treatment. Drug resistance could be driven in part by adaptive redox remodeling of cancer cells. Paradoxically, drug-resistant malignancies exhibit elevated reactive oxygen species (ROS), as well as amplified antioxidant defenses, which enable cancer cell survival under therapeutic stress. Central to this adaptation is glutathione (GSH), the predominant cellular antioxidant, whose synthesis relies on sulfur-containing amino acids (SAAs) – methionine and cysteine. This review delineates the metabolic interplay between methionine and cysteine in the transsulfuration pathway, highlighting their roles as precursors in GSH biosynthesis. We systematically summarize the key enzymes that drive GSH production and their contributions to resistance against platinum-based drugs and other chemotherapeutics. In addition to GSH synthesis, we summarize the roles of GSH antioxidant systems, including glutathione peroxidases (GPXs), peroxiredoxins (PRDXs), and thioredoxins (TRXs), which are critical in chemotherapeutic drug resistance through ROS scavenging. Recent advances reveal that targeting these enzymes, by pharmacologically inhibiting transsulfuration enzymes or disrupting GSH-dependent antioxidant cascades, can sensitize resistant cancer cells to ROS-mediated therapies. These findings not only clarify the mechanistic links between SAA metabolism and redox adaptation but also provide practical approaches to overcome chemotherapeutic drug resistance. By analyzing metabolic and redox vulnerabilities, this review highlights the therapeutic potential to restore chemosensitivity, offering new options in precision oncology medicine.