<![CDATA[Lung cancer remains the leading cause of cancer-related mortality worldwide, with Epidermal Growth Factor Receptor (EGFR) mutations, particularly L858R, driving the progression and drug resistance of non-small cell lung cancer (NSCLC). Ficus minahassae (Langusei), an endemic species of North Sulawesi, contains diverse bioactive metabolites whose anticancer potential has not been explored. This study evaluated the potential of Langusei fruit metabolites as EGFR L858R inhibitors through an integrative in silico approach. Metabolites were identified via gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–high-resolution mass spectrometry (LC–HRMS). Target prediction was conducted using SwissTargetPrediction (probability > 0.5) and the Similarity Ensemble Approach (SEA) (MaxTC > 0.5), while NSCLC-related targets were retrieved from OMIM, GeneCards, Genpia2, DisGeNET, and cBioPortal. Network pharmacology and CytoHubba topology analyses were used to identify hub proteins, followed by ADMET profiling and molecular docking to assess binding affinity toward EGFR wild type and L858R mutant. A total of 170 metabolites were identified, dominated by fatty acyls, prenol lipids, and steroid derivatives. Integration of target prediction and disease databases revealed 355 overlapping proteins, among which seven hub proteins, including EGFR, STAT3, EP300, HSP90AA1, JUN, HIF1A, and ESR1, were identified as key regulators of oncogenic pathways. Molecular docking demonstrated that (Z)-1-(1,3-benzodioxol-5-yl)-3-methoxy-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one exhibited strong binding affinities to both EGFR wild type and L858R mutant and possessed a favorable ADMET profile comparable to Gefitinib and Osimertinib. These findings highlight Langusei fruit as a promising natural source of safe, multi-target EGFR inhibitors with potential therapeutic relevance for NSCLC. Further in vitro and in vivo validation is warranted to confirm efficacy and selectivity.]]>
