Rethinking hyperhomocysteinemia: from causal risk factor to biomarker of glutathione deficiency in chronic diseases.

Hyperhomocysteinemia (HHcy) is a common metabolic disorder characterized by systemic elevation of the thiol amino acid homocysteine. Although HHcy is recognized as an independent risk factor for cardiovascular and many other chronic diseases, the causes and underlying mechanisms remain unclear despite decades of extensive research. The objective of this review is to critically examine the available literature in order to explore the hypothesis that endogenous glutathione deficiency may represent a primary pathological condition underlying hyperhomocysteinemia. Glutathione (GSH) is a tripeptide composed of the amino acids glycine, cysteine, and glutamate. GSH primarily serves as a master antioxidant, protecting cells from free radicals and playing a crucial role in maintaining redox homeostasis. Beyond its antioxidant properties, GSH plays a crucial role in numerous cellular processes, making it essential for health and for addressing age-related chronic diseases. The review examines into the redox regulation of homocysteine production and the connection between homocysteine and glutathione metabolism, while also addressing methodological aspects of homocysteine and glutathione measurement and the pre‑analytical and analytical challenges associated with their reliable quantification in clinical settings. It also includes a critical analysis of current experimental HHcy models and their relevance for extrapolation to humans. It is concluded that experimental HHcy is confounded by oxidative stress, a pathological condition that results from, contribute to, or be exacerbated by decreased endogenous glutathione levels. A strong negative correlation between homocysteine and glutathione has been demonstrated, and restoration of endogenous glutathione through nutritional interventions is associated with normalization of blood homocysteine. The literature indicates that the same environmental factors that induce oxidative stress and GSH depletion also activate redox‑sensitive enzymes in the methionine cycle and transsulfuration pathway, thereby driving the metabolic shift toward hyperhomocysteinemia. Consequently, these enzymes facilitate the production of homocysteine and its conversion into cysteine, supplying the rate-limiting substrate essential for glutathione biosynthesis. In this context, hyperhomocysteinemia can be considered an indicator of metabolic reprogramming aimed at restoring disrupted redox homeostasis by supporting glutathione biosynthesis, thereby alleviating oxidative stress and its associated pathological changes. The review concludes by outlining the evidence supporting the view that glutathione deficiency, rather than hyperhomocysteinemia, may constitute the primary underlying abnormality in chronic human diseases. The concept of glutathione depletion as a Trojan horse" challenges the prevailing paradigm that attributes disease pathogenesis primarily to hyperhomocysteinemia. Instead, this condition may be better understood as a risk factor for chronic diseases, given that its underlying mechanisms appear to stem from disrupted redox homeostasis and cellular glutathione deficiency. From a practical standpoint, homocysteine measurement offers a simpler and more accessible laboratory surrogate than direct glutathione assessment for screening individuals with potential GSH deficiency. However, fully realizing the clinical utility of this approach will require further research into the molecular mechanisms by which glutathione depletion drives hyperhomocysteinemia. Elucidating these mechanisms could open genuine and cost‑effective opportunities for the prevention and treatment of chronic diseases by shifting the therapeutic focus from homocysteine to glutathione metabolism.