Elucidating the multiscale mechanisms and therapeutic targets of caffeic acid in gastric cancer: a synergy of computational and experimental approaches.

[INTRODUCTION] Gastric cancer is a malignant tumor with high incidence and mortality rates worldwide, and effective therapeutic strategies targeting its complex pathological processes are limited. Caffeic acid is a phenolic compound derived from natural plants and has attracted attention for its potential anticancer properties; however, its mechanism of action in gastric cancer has not been fully elucidated.

[METHODS] In this study, a multimodal computational framework integrating multiomics, machine learning, and molecular dynamics simulations, combined with experiments, was used to systematically investigate the molecular mechanism of caffeic acid against gastric cancer.

[RESULTS] Among the predicted targets, FZD2-a major receptor that mediates noncanonical WNT/Ca2+ signaling-was identified as a core regulatory hub associated with tumor progression and metastasis. Molecular dynamics simulations further revealed a stable binding interaction between caffeic acid and FZD2. An in vitro EMT model was established by treating human gastric cancer cells with TGF-β1. The results showed that caffeic acid intervention inhibited cell migration, invasion, and EMT progression while reducing FZD2 protein expression.

[DISCUSSION] This study confirmed that caffeic acid regulates FZD2 expression and inhibits the activation of the noncanonical Wnt5a/Ca/NFAT signaling pathway, thereby interfering with gastric cancer-related pathological processes. These findings reveal the molecular mechanism of caffeic acid in gastric cancer and reflect the value of natural products in cancer research.