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

Key findings from this study

• The review identifies that polyphenols modulate oxidative stress and inflammation through integrated direct antioxidant mechanisms, redox signaling pathway activation, and endogenous enzymatic defenses.
• The authors propose that bioavailability, microbiota-mediated biotransformation, and dose realism are primary—not secondary—determinants of in vivo therapeutic relevance.
• The framework establishes that clinical benefits of polyphenol interventions vary considerably across cardiometabolic, cognitive, and immunometabolic contexts, requiring context-specific evidence evaluation rather than universal claims.

Overview

This review synthesizes evidence on plant polyphenols, particularly flavonoids, as bioactive compounds in preventive and complementary therapeutic applications. The analysis integrates direct antioxidant mechanisms (radical scavenging, metal chelation), redox signaling pathways (Keap1-Nrf2/ARE, inflammatory cascades), endogenous antioxidant enzyme regulation, and mitochondrial quality control. The review emphasizes evidence-based synthesis supported by structured summary tables documenting limitations, contradictions, and context dependencies across in vitro, in vivo, and human studies, distinguishing reported clinical benefits from preliminary findings.

Methods and approach

The authors conducted a comprehensive literature synthesis integrating multiple mechanistic frameworks: direct antioxidant chemistry through hydrogen atom transfer, single-electron transfer, and metal chelation; redox signaling via Keap1-Nrf2/ARE and inflammatory pathways; endogenous antioxidant enzyme systems; and mitochondrial quality control mechanisms. Evidence evaluation spanned in vitro, in vivo, and human studies. The review prioritized bioavailability, microbiota-driven biotransformation, and dose realism as primary determinants of physiological relevance. Structured summary tables explicitly detailed study limitations, contradictions, and context dependencies to support reproducible interpretation.

Results

Polyphenols exert antioxidant effects through multiple converging mechanisms: direct radical scavenging, activation of endogenous antioxidant defenses via Nrf2 signaling, and modulation of inflammatory pathways implicated in cardiovascular disease, cancer, neurodegeneration, and metabolic disorders. Representative flavonoids and dietary sources are documented across cardiometabolic, cognitive, neuroprotective, and immunometabolic contexts. Clinical interventions and nutraceutical applications demonstrate variable efficacy depending on bioavailability constraints and microbiota-driven metabolite profiles.

The review identifies critical gaps between in vitro potency and in vivo clinical utility. Bioavailability limitations, interindividual microbiome variability, and dose-response relationships emerge as primary determinants of therapeutic relevance. Structured evidence synthesis reveals that reported benefits in some contexts remain well-supported, whereas claims in other therapeutic areas rely on preliminary findings lacking robust clinical endpoints.

Implications

Bioavailability, microbiota-driven biotransformation, and dose realism must be repositioned as primary rather than secondary considerations in polyphenol research. This reframing directly impacts the translation of nutraceutical and therapeutic applications from bench findings to clinical practice. Interventions designed without explicit attention to these determinants risk inefficacy or irreproducibility in target populations.

Future research requires standardized exposure characterization, comprehensive metabolite profiling, dose-appropriate intervention design, and harmonized clinical endpoints. Stratification strategies accounting for microbiome-driven interindividual variability are essential to improve reproducibility and inform evidence-based therapeutic use. Without these methodological advances, polyphenol-based therapeutics will remain limited in clinical applicability despite mechanistic promise.

Scope and limitations

This summary is based on the study abstract and available metadata. It does not include a full analysis of the complete paper, supplementary materials, or underlying datasets unless explicitly stated. Findings should be interpreted in the context of the original publication.