Polyphyllin I in malignant tumors: molecular mechanisms and advances

Natural products derived from traditional Chinese medicine have become an important focus in anticancer drug discovery due to their favorable safety profiles and multi-target properties. Polyphyllin I (PPI), a major bioactive constituent of Rhizoma Paridis (Chong-lou), represents the key pharmacological basis for its traditional uses, including heat-clearing, detoxification, and anti-inflammatory effects. Extensive pharmacological studies have shown that PPI exhibits a variety of biological activities, such as anti-inflammatory and immunomodulatory effects. Among these, its broad-spectrum antitumor activity has received particular attention.

This review systematically summarizes the structure-activity relationships, multi-target antitumor mechanisms, and druggability of PPI. It also aims to provide a reference for future research on structural optimization, deeper mechanistic exploration, novel formulation development, and combination therapy strategies.

A systematic literature search was performed in PubMed, Web of Science, and CNKI from database inception to March 2026. The search strategy used combinations of the following keywords: "Polyphyllin I," "tumor," "apoptosis," "autophagy," "migration and invasion," "oxidative stress," "ferroptosis," "epithelial-mesenchymal transition," "drug resistance reversal," "drug synergy," "druggability," and "pharmacokinetics." Studies were eligible for inclusion if they were original research articles investigating PPI and fulfilled at least one of the following criteria: (1) analysis of structure-activity relationships; (2) pharmacodynamic evaluation using cell, animal, or organoid models; (3) investigation of the molecular mechanisms underlying its antitumor effects; or (4) assessment of its druggability. Studies were excluded if they met any of the following criteria: (1) non-peer-reviewed publications, conference abstracts, editorials, letters to the editor, or duplicate reports; (2) studies that did not investigate the antitumor effects of PPI; or (3) studies based solely on bioinformatic predictions from public databases without experimental validation in cellular or animal models.

Preclinical studies have shown that PPI exerts broad-spectrum antitumor effects through multiple mechanisms. These include induction of apoptosis and autophagy, suppression of tumor cell migration, invasion, and epithelial-mesenchymal transition, regulation of oxidative stress homeostasis, induction of ferroptosis, reversal of multidrug resistance, and synergistic effects with chemotherapeutic agents. Overall, this review systematically summarizes the structure-activity relationships, antitumor mechanisms, and druggability of PPI, providing a reference for future research on this promising natural compound.

This review fills a gap in the existing literature by providing a systematic overview of PPI from three perspectives: structure-activity relationships, antitumor mechanisms, and druggability. It offers a theoretical basis for the development of novel PPI-derived anticancer lead compounds and for the design of multimodal combination therapeutic strategies. At present, research on PPI remains at the preclinical stage. Further studies are needed to clarify its molecular targets, evaluate its safety profile, and characterize its pharmacokinetics. These efforts will be essential for advancing PPI toward the development of preclinical lead candidates.