How Polyphenol Metabolites Spatiotemporally Reprogram Transcription Factors and Human Proteostasis: A Metabolite-Centric Framework

Polyphenols act in humans through authentic metabolites, including regio-isomeric glucuronides/sulphates, O-methylated forms, and microbiota products (urolithins, γ-valerolactones, equol), that reach targets by spatiotemporally gated exposure. Vectorial transport (MRP2/BCRP/P-gp), enterohepatic cycling, and β-glucuronidase hubs create early, surface-proximal microbursts of aglycone/catechol, whereas microbiota metabolites arrive systemically 6–24 h later. Signalling emerges from a continuum of weak noncovalent modulation, conditionally gated electrophile/redox relays (catechol → o-quinone, reversible Michael adduction plus signalling-range H2O2), and PTM cascades (phosphorylation → acylation → proteostasis) that reprogram NRF2/Keap1, NF-κB/IKK, AMPK/MAPK/PI3K-Akt, SIRT1/HDACs, PPARγ, AhR, and TFEB according to where and when metabolites appear. We provide methods and standards to dose isomer-resolved metabolites at physiological free concentrations (nM-low µM) in transport-competent systems, with PK-informed sampling across seconds–minutes, 15/60/240 min, and 6–24 h, and we outline a research agenda (reference panels, spatial exposure atlases, metabotype-stratified trials, safety windows). Framed this way, polyphenols shift from vague “antioxidants” to programmable dietary signals that enable precision nutrition targeting transcription-factor and proteostasis programmes in vivo.