<i>Polygonum barbatum</i> extract induces ER stress-mediated UPR and autophagy to suppress colorectal cancer growth

<i>Polygonum barbatum</i> extract (PBE) is a traditional herbal remedy historically used for its analgesic, anti-inflammatory, and diuretic effects. However, its anticancer potential and underlying molecular mechanisms in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrate that PBE exerts potent cytotoxicity in CRC cells by inducing both the unfolded protein response (UPR) and autophagy. In vitro, PBE treatment resulted in a dose-dependent reduction of cell viability and colony formation in multiple CRC cell lines. Moreover, in a HCT116 xenograft mouse model, oral administration of PBE significantly inhibited tumor growth without inducing overt toxicity. Mechanistically, PBE increased the accumulation of acidic vesicular organelles and upregulated key UPR regulators-including BiP, IRE1, and PERK-accompanied by enhanced conversion of LC3-I to LC3-II and reduced p62 levels, indicative of elevated autophagic flux. Notably, co-treatment with chloroquine, an autophagy inhibitor, partially rescued cell viability, underscoring that autophagy contributes to PBE-induced cell death. In addition, PBE modulated several critical signaling pathways by inhibiting EGFR, mTOR, and STAT3 while concurrently activating downstream ERK and the AMPK-ACC axis. Collectively, these results reveal that PBE triggers ER stress-mediated UPR and autophagy to promote autophagic cell death in CRC, supporting its potential development as a novel therapeutic agent for colorectal cancer.