Evolution of public health paradigms in folic acid application: from nutritional deficiency correction to systemic metabolic optimization

Folate, an essential micronutrient, has undergone substantial evolution in both scientific understanding and clinical application over the past several decades. This review delineates three major paradigms that have shaped the clinical and public health use of folic acid. Paradigm I centers on the correction of diseases caused by absolute folate deficiency, such as neural tube defects and megaloblastic anemia, grounded in folate’s fundamental role in nucleotide synthesis and cell division. Paradigm II expands the role of folate to the prevention of common chronic diseases, particularly hypertension accompanied by elevated homocysteine (H-type hypertension) and stroke, mediated through homocysteine metabolism, and supported by large-scale randomized clinical trials. Paradigm III advances a system-level understanding of folate biology, emphasizing that its health effects depend on a coordinated metabolic network involving key cofactors, including vitamin B12, vitamin D, and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. This paradigm highlights the importance of nutrient interactions, genetic variability, and metabolic context in determining health outcomes. Building on these advances, we propose a novel conceptual framework—“FOLATE 3.0”, which represents a precision, synergistic nutritional strategy integrating folate, vitamin B12, and vitamin D3 to optimize metabolic health and reduce disease risk. This paradigm shift reflects the transition from one-size-fits-all supplementation to individualized, systems biology-informed, precision nutrition approaches.