Significance: Thioredoxin (Trx) is a powerful antioxidant that reduces protein disulfides to maintain redox stability in cells and is involved in regulating multiple redox-dependent signaling pathways. Recent Advance: The current accumulation of findings suggests that Trx participates in signaling pathways that interact with various proteins to manipulate their dynamic regulation of structure and function. These network pathways are critical for cancer pathogenesis and therapy. Promising clinical advances have been presented by most anticancer agents targeting such signaling pathways. Critical Issues: We herein link the signaling pathways regulated by the Trx system to potential cancer therapeutic opportunities, focusing on the coordination and strengths of the Trx signaling pathways in apoptosis, ferroptosis, immunomodulation, and drug resistance. We also provide a mechanistic network for the exploitation of therapeutic small molecules targeting the Trx signaling pathways. Future Directions: As research data accumulate, future complex networks of Trx-related signaling pathways will gain in detail. In-depth exploration and establishment of these signaling pathways, including Trx upstream and downstream regulatory proteins, will be critical to advancing novel cancer therapeutics. Antioxid. Redox Signal. 38, 403-424.
Keywords: apoptosis; cancer; ferroptosis; oxidative stress; redox; thioredoxin.