Exploring the antitumor effect of curcumin-piperlongumine hybrid molecule (CP) on EGFR-TKI-resistant non-small cell lung cancer using network pharmacological analysis and experimental verification

• • CP suppresses phosphorylation of EGFR, PI3K, AKT, and GSK-3β, directly disrupting the PI3K/AKT signaling axis that drives acquired resistance to third-generation EGFR-TKIs; this dual-pathway blockade is clinically relevant because bypass activation of PI3K/AKT accounts for a substantial fraction of osimertinib failures. • • Network pharmacology identified 10 core targets (EGFR, SRC, PIK3R, PIK3CA, KDR, MET, GRB2, PIK3CB, HSP90AA1, ITGB1) with KEGG enrichment converging on PI3K/AKT; this target set overlaps with known resistance drivers such as MET amplification and SRC activation, indicating CP may address multiple resistance mechanisms simultaneously. • • CP induces G2/M phase cell cycle arrest and apoptosis in AZD9291-resistant NSCLC cells at concentrations exceeding the activity of parent compounds curcumin and piperlongumine; the hybrid scaffold therefore overcomes the poor bioavailability and modest potency that have historically limited clinical translation of these natural products. • • In vivo xenograft experiments confirmed growth inhibition of EGFR-TKI-resistant lung cancer, establishing that CP's activity is not an artifact of monolayer culture; however, the study does not report pharmacokinetic parameters (AUC, Cmax, half-life) or toxicity thresholds, which are prerequisites for advancing to IND-enabling studies.