Deuterium-depleted water (DDW) refers to water with a deuterium abundance lower than that of natural water, which is approximately 150 ppm.In recent years, DDW has shown certain therapeutic potential in the treatment of major diseases such as tumors, neurodegenerative diseases, endocrine and metabolic diseases, and cardiovascular diseases, but its mechanisms of action remain incompletely elucidated. Oxidative stress is a pathological state caused by an imbalance between reactive oxygen species (ROS) generation and antioxidant defense, and is a common mechanism underlying the development and progression of multiple chronic diseases. Mitochondria, as the core organelles for cellular energy metabolism and ROS generation, have proton transport, membrane potential changes, and electron transfer efficiency that are closely related to the intracellular deuterium-to-protium (D/H) ratio. Therefore, elucidating the biological effects of DDW from the perspective of redox homeostasis is of great significance for understanding its therapeutic applications. This review systematically summarizes the isotopic effects of water, the fundamental physicochemical properties of DDW, the modes of cellular uptake, and the research progress on DDW in various diseases, with a particular emphasis on analyzing the potential mechanisms by which DDW, through modulating the intracellular deuterium-to-hydrogen (D/H) ratio, affects intracellular redox homeostasis, mitochondrial function, cell cycle progression, apoptosis, autophagy, senescence, and inflammatory responses. Current evidences indicate that DDW exerts positive effects in antitumor, neuroprotection, erythropoiesis, regulation of glucolipid metabolism, cardiovascular protection, as well as anti-inflammatory and detoxification processes. These effects are largely associated with alterations in oxidative stress levels, remodeling of mitochondrial function, and modulation of the antioxidant defense system, suggesting that regulation of redox homeostasis may represent an important entry point for DDW-assisted disease intervention. Nevertheless, current research on DDW still suffers from several limitations, including substantial heterogeneity in deuterium concentrations, administration durations, and timing of intervention across different studies, insufficient evidence for long-term safety, limited clinical sample sizes, a lack of systematic validation of the underlying mechanisms, and relatively high production costs. Future efforts should center on the core scientific question of redox homeostasis regulation, integrating stable isotope tracing, metabolomics, redoxomics, mitochondrial function assessment, and multicenter randomized double-blind clinical trials to further clarify the indications, optimal dosage regimens, regulatory mechanisms, safety profile, and translational potential of DDW. This review may provide a reference for understanding the current research status and future developmental challenges of DDW as a potential adjuvant therapy for major diseases from the perspective of redox homeostasis regulation.

Key words: Deuterium-depleted water, Redox homeostasis, Mitochondrial function, Major diseases, Therapy