Taichunamide‐A Inhibits Stomach Cancer Growth Through AKT/MAPK Pathway Suppression and EGFR Inhibitor Synergy

Stomach cancer remains the leading cause of cancer-related mortality worldwide and necessitates the development of novel therapeutic agents. Marine-derived natural products as promising anticancer agents. In this study, we investigated the potential therapeutic effects of taichunamide-A (TAI-A), a marine fungal metabolite isolated from Aspergillus taichungensis 299, against stomach cancer. We evaluated the anticancer properties of TAI-A in AGS and HGC-27 stomach cancer cell lines using cell viability, flow cytometry, and colony formation assays. The molecular mechanisms were investigated using RNA sequencing, pathway analysis, qPCR, and Western blot analysis. We also assessed the potential synergistic effects of TAI-A and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. TAI-A demonstrated potent antiproliferative activity against stomach cancer cells (EC₅₀: AGS = 0.35 μM, HGC-27 = 0.23 μM) and significantly suppressed colony formation. Mechanistic studies revealed that TAI-A induced apoptosis through simultaneous inhibition of the AKT and MAPK signaling pathways. Transcriptomic analysis revealed the downregulation of cell cycle-related genes and enrichment of apoptotic pathways. Notably, TAI-A exhibited synergistic effects with erlotinib, enhancing antitumor activity by inducing apoptosis. Our findings established TAI-A as a promising anticancer agent that targets multiple oncogenic pathways in stomach cancer. The synergistic interaction with EGFR inhibitors suggested potential therapeutic applications in combination treatment strategies. These results warrant further investigation into TAI-A in preclinical models.