Acteoside suppresses non-small cell lung cancer by upregulating E-cadherin and modulating IL-17/STAT3 signaling

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, hindered by drug resistance and metastasis. Epithelial-mesenchymal transition (EMT) drives NSCLC progression and therapy resistance, but few effective EMT-targeting strategies exist. Acteoside, a phenylethanoid glycoside has shown promising antitumor activity, but its specific mechanisms in NSCLC remain unclear. This study aimed to define the anti-NSCLC potency of acteoside, uncover its mechanism, and appraise its translational value. In vitro proliferation assays and distinct xenografts (monotherapy and Baihe Gujin Decoction) quantified efficacy. Integrative transcriptomics, proteomics, western blot, molecular dynamics, surface plasmon resonance (SPR) assay and knockdown experiment mapped the mode of action, while in vivo HPLC-MS/MS-based pharmacokinetic (PK) profiling gauged bioavailability. Functional validation supported that acteoside inhibited NSCLC cell migration in Transwell assays. Acteoside, identified as the key bioactive compound in Baihe Gujin Decoction, demonstrated potent anti-NSCLC efficacy both in vitro and in vivo. It inhibited A549 cell proliferation (IC50 = 3.79 µM), induced apoptosis and G0/G1 arrest, and significantly suppressed tumor growth in xenograft models without toxicity. Pharmacokinetic studies revealed acteoside acts as a prodrug, rapidly converting to caffeic acid. Multi-omics, IL-17 pathway perturbation assay and molecular analyses supported that acteoside upregulates E-cadherin (CDH1) via IL-17 pathway inhibition, with stable binding to the E-cadherin dimer interface validated by molecular dynamics, SPR, knockdown experiment and Western blot. Transwell assays functionally validated EMT modulation and migration inhibition. These findings provide evidence for acteoside as a novel small-molecule CDH1 modulator for NSCLC treatment. Acteoside is an antitumor agent that suppresses cancer cell proliferation and induces tumor regression in preclinical models, with no overt toxicity observed at the tested doses. Mechanistically, acteoside upregulates E-cadherin (CDH1) expression and directly binds to the CDH1 protein with measurable affinity, while also modulating the IL-17 signaling pathway. Pharmacokinetic studies indicate that acteoside undergoes extensive metabolism after oral administration, with its metabolite caffeic acid reaching higher systemic exposure, suggesting a potential prodrug characteristic. These findings position acteoside as a promising candidate for CDH1-targeted therapeutic strategies in non-small cell lung cancer (NSCLC), warranting further investigation.