Food-Derived Flavonoids Show Predicted Allele-Dependent Interaction Profiles With a Candidate EEF1A2 Codon 361 Alteration Cluster in Intrahepatic Cholangiocarcinoma

Abstract

Food-derived flavonoids are of increasing interest as bioactive compounds relevant to nutraceutical and functional-food research, but mutation-aware prioritization of such compounds remains limited in intrahepatic cholangiocarcinoma (CCA). Whole-exome sequencing data from seven tumor-normal matched CCA pairs were reanalyzed and integrated with mutation annotation, structural mapping, cell-based assays, molecular docking, and 100-ns molecular dynamics simulations. The cohort showed marked intertumoral heterogeneity, with 324–1244 nonsilent mutations per tumor. A recurrent cluster of EEF1A2 alterations was identified within codons 353–393, including codon 361 substitutions observed in three tumors. Because these codon 361 events involved adjacent nucleotides within the same codon and phasing information was unavailable in the public dataset, the pattern is interpreted conservatively as a candidate recurrent alteration cluster rather than a validated driver hotspot. In HuCCT-1 cells, the ectopic expression of EEF1A2-I361M or EEF1A2-I361L increased proliferation and wound closure relative to wild-type EEF1A2, with I361M showing a stronger phenotype. Structure-guided docking and molecular dynamics simulations further suggested predicted allele-dependent interaction profiles of luteolin, morin, and taxifolin near the mutated region. These computational results are presented as hypothesis-generating prioritization outputs and not as proof of direct target engagement or allele-selective biological activity. Overall, the findings identify EEF1A2 codon 361 as a candidate molecular context for future validation of food-derived flavonoids in CCA-related research.