A monoterpenoid dihydrochalcone derivative isolated from Conamomum rubidum sensitizes erlotinib-mediated lung cancer cell death by suppressing STAT3/Bcl-2 signaling

• Compound 1 exerts strong cytotoxicity in EGFR-mutant and −resistant NSCLC cells. • Compound 1 restores erlotinib responsiveness via STAT3 pathway suppression. • Compound 1 inhibits both phosphorylated and acetylated forms of STAT3. • Compound 1 downregulates STAT3-dependent anti-apoptotic Bcl-2 expression. • Molecular docking and dynamics confirm compound 1–STAT3 SH2 domain interaction. Resistance to erlotinib remains a major challenge in the treatment of non-small cell lung cancer (NSCLC), often driven by persistent activation of STAT3-mediated pro-survival signaling. Compound 1, a monoterpenoid dihydrochalcone derivative isolated from Conamomum rubidum , has demonstrated cytotoxic potential; however, its ability to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has not yet been elucidated. This study aimed to evaluate the anticancer effects of compound 1, its capacity to restore erlotinib sensitivity in NSCLC, and the underlying molecular mechanisms. Cytotoxicity and combination drug assays were conducted in A549 and H1975 cells, while apoptosis was assessed using Annexin V-FITC/propidium iodide (PI) staining. Network pharmacology, molecular docking, and molecular dynamics simulations were performed to predict compound 1 targets and binding stability, followed by target validation through immunoblotting. The compound’s efficacy was further examined in erlotinib-resistant HCC827 cells. Compound 1 significantly reduced NSCLC cell viability and enhanced erlotinib-induced apoptosis by suppressing both phosphorylated activator of transcription 3 (p-STAT3) and acetylated STAT3 (a-STAT3), leading to downregulation of Bcl-2. Molecular docking and simulation analyses suggested favorable interactions of compound 1 in a region proximal to the STAT3 SH2 domain, supporting STAT3 as a potential target. Moreover, compound 1 resensitized erlotinib-resistant HCC827 variants to erlotinib-induced cell death. Compound 1 exhibits potent cytotoxic and chemosensitizing effects by suppressing the STAT3/Bcl-2 signaling axis. These findings suggest that compound 1 may represent a promising therapeutic candidate for overcoming EGFR-TKI resistance in NSCLC.