Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases and frequently associated with poor outcomes due to resistance to conventional therapies. The epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) axis plays a central role in NSCLC progression by activating downstream phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling, thereby promoting survival and proliferation. Natural compounds have emerged as promising modulators of these pathways, and oxyresveratrol (OXY), a hydroxylated analog of resveratrol, has been reported to possess antioxidant and anticancer properties, though its mechanistic role in NSCLC remains unclear. In this study, we investigated the effects of OXY in EGF-stimulated A549 and H1299 cells. OXY significantly reduced metabolic activity and decreased cell number in a dose-dependent manner and increased the proportion of apoptotic cells. Mechanistically, OXY selectively attenuated EGF-induced AKT phosphorylation while largely sparing extracellular signal-regulated kinase 1/2 (ERK1/2) activation and did not measurably alter EGFR phosphorylation or receptor trafficking dynamics. These findings indicate that OXY exposure is associated with AKT-selective signaling suppression and reduced cellular fitness in NSCLC cells, without evidence of direct EGFR inhibition. Further genetic rescue and pathway-epistasis studies are required to establish causal dependency on AKT signaling and to support in vivo validation.
