Five plant-derived polyphenols — resveratrol, curcumin, naringenin, quercetin, and EGCG — demonstrate preclinical capacity to slow cyst growth in autosomal dominant polycystic kidney disease (ADPKD) by simultaneously suppressing inflammation, aberrant cell proliferation, fibrosis, and dysregulated energy metabolism. Notably, naringenin shows direct interaction with the polycystin-2 channel — the very protein mutated in ADPKD — while quercetin clears senescent cells that accelerate disease progression. A clinical curcumin trial failed not due to biological inefficacy but insufficient renal bioavailability, a pharmacokinetic ceiling that undermined the compound before it could act.
ADPKD affects roughly 1 in 400–1,000 people globally and progresses relentlessly toward renal failure, with tolvaptan remaining the only approved disease-modifying therapy, constrained by hepatotoxicity risks. The multi-pathway nature of cyst expansion has long frustrated single-target drug development, making polyphenols' pleiotropy conceptually attractive. However, this is a narrative review — not a meta-analysis or original trial — meaning it synthesizes existing evidence without new data or pooled statistics, limiting causal conclusions. The field remains firmly in preclinical territory for most compounds. The naringenin-polycystin-2 interaction is the most mechanistically compelling lead here, warranting dedicated human pharmacokinetic studies. Nanoformulation strategies to enhance renal delivery could be genuinely transformative if they resolve the bioavailability problem that sank the curcumin trial. Overall, this is confirmatory rather than paradigm-shifting — but it maps a credible combinatorial roadmap for a disease badly in need of new options.
