Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy

The thioredoxin (Trx) system, an integral component of cellular redox regulation, preserves protein dithiol-disulfide equilibrium through its conserved Cys-Gly-Pro-Cys active site and is involved in key cellular functions, including cell proliferation, apoptosis, and signal transduction. In cancer biology, the thioredoxin system plays dual roles: overexpression can suppress oxidative stress and promote tumor growth, whereas dysfunction can trigger programmed cell death (PCD). However, a critical area for future research is to delineate how Trx modulates the intricate networks of PCD, and to identify key nodes within these pathways that can be targeted for oncological therapy. This review outlines the structure and function of the thioredoxin system, highlighting its role in redox balance and its regulatory dynamics in healthy and disease states. We further examine the dual role of Trx by detailing its cross-regulatory networks that modulate diverse PCD pathways, including disulfidptosis, ferroptosis, apoptosis, autophagy, pyroptosis and necroptosis. In addition, we comprehensively outline therapeutic approaches that manipulate the Trx pathway to regulate PCD across a spectrum of health disorders, including malignancies, infectious diseases, neurodegenerative conditions, cardiovascular ailments, and metabolic dysfunctions. Finally, we address the current clinical applications of targeting the thioredoxin system. Although challenges such as tumor heterogeneity and drug-delivery efficiency persist, it remains a promising therapeutic avenue. This review aims to develop a theoretical framework and provide tactical guidance for the development of novel treatments targeting the Trx-PCD pathway.