A Small Molecular Weight Saccharide Fraction From Panax quinquefolium L. Inhibited Non‐Small Cell Lung Cancer via Endoplasmic Reticulum‐Stress Mediated Apoptosis

Non-small cell lung cancer remains a significant global health challenge. The limited efficacy, drug resistance, and toxicity of current treatments highlight the need for novel therapeutics. While Panax quinquefolium L. has demonstrated anti-tumor activity in previous studies, the therapeutic potential of its small molecular weight saccharide fraction (SFPQ) remains unexplored. This study investigates the anti-tumor efficacy and mechanisms of SFPQ, aiming to establish its potential as a novel anti-cancer agent. SFPQ was isolated via macroporous resin adsorption and ultrafiltration, then characterized by LC-MS/MS analysis. In vitro cytotoxicity was assessed using CCK-8 and colony formation assays, and apoptosis was quantified via flow cytometry. Live-cell fluorescent labeling and confocal microscopy confirmed the specificity of SFPQ for the endoplasmic reticulum. Mechanistic insights into endoplasmic reticulum stress were elucidated via bioinformatics analysis, Western blot, and RT-qPCR assays. Lentiviral transduction and pharmacological inhibition validated SFPQ-mediated regulation of IRE1/JNK phosphorylation and c-Myc expression. In vivo anti-tumor efficacy and safety were assessed using xenograft models, complemented by morphometric parameters analysis and histopathology. CCK-8 and colony formation assay demonstrated cytotoxic effects of SFPQ on non-small cell lung cancer cells. SFPQ significantly promoted endoplasmic reticulum Ca²⁺ efflux, altered endoplasmic reticulum morphology, and increased the apoptosis rate for A549 cells. Live-cell imaging confirmed strong endoplasmic reticulum affinity, while mechanistic studies demonstrated that SFPQ triggered endoplasmic reticulum stress-mediated apoptosis via the IRE1/JNK/c-Myc axis. In xenograft models, SFPQ significantly reduced tumor volume and weight in a dose-dependent manner, showing comparable efficacy to cisplatin. Histopathological analysis further confirmed SFPQ's favorable safety profile. This study elucidates the endoplasmic reticulum stress-mediated anti-lung cancer mechanism of SFPQ through IRE1/JNK/c-Myc signaling. SFPQ exhibits potent anti-lung cancer activity in vitro and in vivo with minimal systemic toxicity, supporting its potential as a novel therapeutic agent.