The Therapeutic Architecture of Chlorogenic Acids: Molecular Mechanisms in Chronic Disease Prevention

This review examines the structural variety, distribution, and physicochemical properties of chlorogenic acids (CGAs), identifying coffee and green coffee as the leading dietary sources of these compounds. Preclinical studies indicate that plant-derived phenolic compounds exhibit strong antioxidant, anti-inflammatory, neuroprotective, cardioprotective, and antidiabetic effects across various disease models. The biological effectiveness of CGAs is attributed to their modulation of cellular signaling pathways, particularly by activating the erythroid 2-related factor 2 antioxidant defense mechanism and inhibiting the pro-inflammatory nuclear factor kappa B pathway. The regulation of the energy-sensing Sirtuin 1 and AMP-activated protein kinase pathways further enhances these therapeutic effects. In the gastrointestinal tract, CGAs serve as key modulators of the microbiota-gut-brain axis by exerting prebiotic-like effects, lowering the Firmicutes/Bacteroidetes ratio, promoting the production of short-chain fatty acids, and preserving gut barrier integrity. Some preclinical studies with coffee, Ilex paraguariensis, Eugenia uniflora, and other CGAs-rich extracts are also discussed. However, despite strong preclinical evidence, translating these findings into human clinical settings remains inconsistent due to significant individual differences in gut microbiota metabolism and the confounding effects of other components in dietary supplements, such as caffeine. Considering this, the review will first explore the molecular mechanisms supporting the potential development of CGAs as preventive interventions, while also discussing current human trials demonstrating selective improvements in neurological, cardiovascular, and metabolic functions. It will also highlight a historical limitation: the lack of studies on the bioavailability, bioactivity, and efficacy of isolated CGAs. The review will conclude by addressing the constraints of clinical studies, emphasizing the urgent need for future precision nutrition frameworks that employ standardized CGAs formulations to enhance potential therapeutic outcomes.