New insights into reductive stress responses and its clinical relation in cancer

Cells are susceptible to both oxidative and reductive stresses, with reductive stress being less studied and potentially therapeutic in cancer. Reductive stress, characterized by an excess of reducing equivalents exceeding the activity of endogenous oxidoreductases, can lead to an imbalance in homeostasis, causing an increase in reactive oxygen species induction, affecting cellular antioxidant load and flux. Unlike oxidative stress, reductive stress has been understudied and poorly understood, and there is still much to learn about its mechanisms in cancer, its therapeutic potential, and how cancer cells react to it. Changes in redox balance and interference with redox signaling are linked to cancer cell growth, metastasis, and resistance to chemotherapy and radiation. Overconsumption of reducing equivalents can reduce metabolism, alter protein disulfide bond formation, disrupt mitochondrial homeostasis, and disrupt cancer cell signaling pathways. Novel approaches to delivering or using cancer medicines and techniques to influence redox biology have been discovered. Under reductive stress, cancer cells may coordinate separate pools of redox pairs, potentially impacting biology.