Journal Article

Tetrastigma Hemsleyanum Polysaccharide Suppresses Triple‐Negative Breast Cancer by Disrupting the Hippo‐YAP/TEAD4‐PDIA4 Axis and Endoplasmic Reticulum Stress Adaptation

Su, Hongmeng, Zhang, Youxue, Ding, Zhishan, Zhang, Huaixi, Jiang, Wei, Wang, Lihong, Si, Wentao, Liu, Jialin, Shang, Yini, Li, Yafei

2026

Overview

Triple‐negative breast cancer (TNBC) exhibits addiction to chronic endoplasmic reticulum (ER) stress, which sustains an aggressive metastatic phenotype through activation of the unfolded protein response (UPR). Here, we identify a previously unrecognized “ER‐stress addiction” axis in which the Hippo pathway effector TEAD4 directly transcriptionally upregulates the ER chaperone PDIA4. We further demonstrate that this axis can be pharmacologically targeted by a natural polysaccharide. Tetrastigma hemsleyanum polysaccharide (THP) selectively activates the Hippo kinase cascade, leading to YAP phosphorylation, cytoplasmic sequestration, and subsequent degradation. This cascade attenuates YAP/TEAD4 interaction and abolishes TEAD4 DNA‐binding activity. Moreover, THP downregulates TEAD4 expression. These combined effects drive transcriptional suppression of PDIA4, catastrophic disruption of ER proteostasis, and ultimately lethal ER stress in TNBC cells. Functionally, THP inhibits migration, invasion, angiogenesis, and intracellular Ca2+ flux in vitro, and—importantly—blocks metastasis in patient‐derived organoids, zebrafish xenografts, and two syngeneic mouse models at non‐toxic doses. Multi‐omics analyses and rescue assays confirm the TEAD4‐PDIA4 axis as the core functional module. Our findings establish THP as a first‐in‐class, natural‐product‐based therapeutic that disrupts ER‐stress addiction in metastatic TNBC by targeting the Hippo‐YAP/TEAD4‐PDIA4 axis. Triple‐negative breast cancer exploits chronic ER stress to drive metastasis. This study identifies a Hippo‐YAP/TEAD4‐PDIA4 axis as a critical mediator of ER‐stress addiction. The natural polysaccharide THP hierarchically disrupts this axis by activating Hippo signaling and downregulating TEAD4, suppressing PDIA4, and triggering lethal ER stress. THP exhibits potent anti‐metastatic efficacy across multiple preclinical models with a favorable safety profile, offering a first‐in‐class therapeutic strategy for metastatic TNBC.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Animals / Breast cancer / Cell Line, Tumor / Chromatography / Cytotoxicity / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Endoplasmic reticulum / endoplasmic reticulum stress / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - genetics / Female / Hippo Signaling Pathway - drug effects / hippo‐YAP pathway / Humans / Kinases / Medical prognosis / Metastasis / Mice / NMR / Nuclear magnetic resonance / Phosphorylation / Polysaccharides - pharmacology / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Signal Transduction - drug effects / Survival analysis / TEA Domain Transcription Factors - genetics / TEA Domain Transcription Factors - metabolism / tetrastigma hemsleyanum polysaccharide / Transcription Factors - genetics / Transcription Factors - metabolism / triple negative breast cancer / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / YAP-Signaling Proteins / Zebrafish