Dietary Polyphenols (Flavonoids) Derived from Plants for Use in Therapeutic Health: Antioxidant Performance, ROS, Molecular Mechanisms, and Bioavailability Limitations

Plant polyphenols, particularly flavonoids, are prominent bioactives in preventive/complementary therapeutic strategies. This article analyzes how some polyphenols can mitigate oxidative stress and inflammation. These processes are involved in cardiovascular disease, cancer, neurodegeneration, and metabolic disorders. Polyphenols are explored through the integration of direct antioxidant chemistry (radical scavenging via hydrogen atom transfer/single-electron transfer/metal chelation), redox signaling (Keap1-Nrf2/ARE and inflammatory pathways), endogenous antioxidant enzyme systems, and mitochondrial quality control. Unlike previous descriptive reviews, a novel aspect of this manuscript is its evidence-based synthesis, fully supported by structured summary tables that explicitly detail limitations, contradictions, and context dependencies in in vitro, in vivo, and human studies, and identify clinically interpretable endpoints for their application. We describe relevant flavonoids and dietary sources, along with functional outcomes in cardiometabolic-cognitive/neuroprotective-immunometabolic contexts. We integrate representative clinical interventions and nutraceutical applications, highlighting where reported benefits are supported and where the evidence is preliminary. Bioavailability, microbiota-driven biotransformation, and dose realism are considered the primary determinants of in vivo relevance, rather than secondary or descriptive considerations. Future research should prioritize standardized exposure and metabolite profile, dose-appropriate interventions, harmonized clinical endpoints, and stratification strategies that account for microbiome-driven interindividual variability to improve reproducibility and inform nutraceutical and therapeutic use.