Abstract
This review synthesizes current evidence on the dualistic and context-dependent roles of selenium-containing antioxidant enzymes-specifically, glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs)-in the development and progression of human cancers. We analyze how these crucial components of cellular redox homeostasis can function as either potent oncogenes or tumor suppressors depending on the tissue of origin, cancer stage, genetic background, and tumor microenvironment. The paradoxical behavior of these enzymes is governed by a complex interplay of transcriptional regulation, epigenetic modifications, and signaling pathway interactions, ultimately influencing critical processes such as apoptosis, proliferation, invasion, and therapy resistance. Special emphasis is placed on the unique role of GPX4 in regulating ferroptosis, a promising target for novel anti-cancer strategies, and on the prognostic significance of TXNRD overexpression in aggressive malignancies. By integrating data across various cancer types, this review highlights these enzyme families as central molecular switches in carcinogenesis and discusses their potential as biomarkers and targets for rational, combination-based therapeutic interventions.