Sappanchalcone Suppresses NSCLC by Oxidative Stress-Driven DNA Damage and ER Stress Activation through PIEZO1 Modulation

Natural compounds are valuable templates for anticancer drug development. Through high-throughput screening of 1,880 natural compounds and structure-activity analysis, we identified sappanchalcone (SC) as a potent agent that induces intracellular calcium elevation and causes G2/M phase arrest in H1975, H1299, and A549 cells. Transcriptomic and protein-protein interaction network analyses revealed multi-target effects of SC, involving oxidative stress, cell cycle dysregulation, and ion homeostasis perturbation. Mechanistically, SC induced ROS accumulation, upregulated the DNA damage, and enhanced the expression of p21 and GADD45α, thereby suppressing the CDK1/Cyclin B1 complex. SC also activated ER stress pathways by phosphorylating IRE1α and PERK. Notably, SC downregulated the mechanosensitive ion channel PIEZO1, and its inhibitor ruthenium red (RR) significantly reversed SC-induced proliferation inhibition and G2/M arrest. This study delineates an antitumor mechanism of SC mediated via a calcium–ER stress–cell cycle axis with translational potential for NSCLC therapy.