# Advances in Understanding Renin–Angiotensin System-Mediated Anti-Tumor Activity of Natural Polyphenols

## TL;DR

This review explores how natural polyphenols fight cancer by balancing the renin–angiotensin system and highlights challenges and solutions for their use.

## Contribution

The paper introduces the dual-regulation of RAS by polyphenols and their autoxidation products as a novel anti-cancer mechanism.

## Key findings

- Polyphenols inhibit the pro-tumor ACE/AngII/AT1R axis while activating the protective ACE2/Ang(1-7)/MasR axis.
- EAOP, a polyphenol oxidation product, shows stronger RAS-modulating effects than the original polyphenols.
- Polyphenols disrupt oncogenic pathways like MAPK and PI3K/Akt/mTOR, reducing tumor growth and oxidative stress.

## Abstract

The imbalance of the renin–angiotensin system (RAS), characterized by the overactivation of the pro-tumor ACE/AngII/AT1R axis, is closely linked to tumor growth, angiogenesis, metastasis, and poor prognosis. Natural polyphenols, such as EGCG and resveratrol, exert anti-cancer effects by dual-regulating RAS: they inhibit the pro-tumor axis by blocking renin, ACE activity, and AT1R expression, while simultaneously activating the protective ACE2/Ang(1-7)/MasR axis. Furthermore, polyphenols and their autoxidation products (e.g., EAOP) modify thiol-containing transmembrane proteins (such as ADAM17 and integrins) and interact with RAS components, further disrupting oncogenic pathways (including MAPK and PI3K/Akt/mTOR) to induce apoptosis, suppress invasion, and reduce oxidative stress. Notably, EAOP exhibits stronger RAS-modulating efficacy than its parent polyphenols. However, challenges such as low bioavailability, insufficient targeting, and limited clinical evidence impede their application. This review provides a comprehensive overview of the anti-cancer mechanisms of polyphenols through RAS regulation, discusses the associated challenges, and proposes potential solutions (including nanodelivery and structural modification) and strategies to advance natural product-based adjuvant treatments.