Quinoa Polyphenols Alleviate Glucose Deprivation‐Induced Endoplasmic Reticulum Stress by Enhancing Hepatic Cellular Autophagy and Antioxidant Capacity

ABSTRACT Glucose deprivation induces ER stress, oxidative damage, and apoptosis, contributing to hepatic dysfunction. This study explores the protective effects and mechanisms of quinoa‐derived polyphenols (QPs) under glucose‐deprived conditions. HepG2 and Huh7 cells were exposed to QPs at 100 or 200 µg/mL for 12 or 24 h under glucose‐deprived conditions, while male mice received QPs by gavage at 40 or 80 mg/kg/day for 14 days, followed by a single intraperitoneal injection of 2‐deoxy‐D‐glucose (2‐DG, 400 mg/kg) to induce ER stress. QPs significantly reduced ER stress markers (GRP78, p‐IRE1, XBP1s), restored mitochondrial membrane potential, and attenuated apoptosis. QPs also activated the Nrf2/HO‐1 antioxidant pathway and improved redox homeostasis. Additionally, QPs enhanced autophagic flux, as evidenced by increased LC3B2, ATG4B, and Beclin 1 and reduced SQSTM1. Pharmacological inhibition studies revealed that autophagy plays a critical role in the QP‐mediated relief of ER stress. In vivo, QPs improved hepatic function and suppressed ER stress induced by 2‐deoxyglucose. QPs protect hepatocytes from glucose deprivation‐induced ER stress and apoptosis by enhancing antioxidant capacity and autophagy. These findings provide new insight into the dietary potential of quinoa polyphenols in preventing metabolic stress‐related liver injury.