Chalcones as multitarget modulators in non-small cell lung cancer: mechanistic insights and therapeutic perspectives

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, and the search for novel therapeutic strategies is ongoing. Chalcones, a class of naturally occurring and synthetically derived open-chain flavonoid precursors, have attracted attention because of their chemical versatility and broad biological activity. This review synthesizes current findings on the molecular mechanisms through which chalcones exert their effects in NSCLC, including modulation of oxidative stress, epithelial-mesenchymal transition, DNA damage responses, and diverse cell death pathways. Chalcones have been shown to interfere with key signaling cascades, such as TGF-β, PI3K/AKT/mTOR, JAK/STAT, and Wnt/β-catenin, with reported effects on tumor proliferation, migration, invasion, and therapy resistance. Their structural flexibility enables chemical optimization aimed at improve potency, selectivity, and pharmacokinetic profiles, supporting further preclinical investigation. Despite promising preclinical results, challenges remain regarding pharmacokinetics, bioavailability, and context-dependent off-target effects. Future research should prioritize integrated mechanistic studies, structure-activity relationship analyses, selective cytotoxicity assessment, and advanced delivery strategies to improve tumor specificity. Chalcones represent chemically versatile multitarget scaffolds for further optimization in NSCLC, particularly in strategies aimed at exploiting epithelial-mesenchymal plasticity, redox adaptation, and regulated cell death.