Naphthoquinone Derivatives from the Endophytic Fungus <i>Fusarium solani</i> Induce Pancreatic Cancer Cells Apoptosis via Targeting EGFR-Mediated PI3K/Akt Pathway

Seven new polyketide compounds, four naphthoquinone derivatives, neofusarubins A-D (<b>1</b>, <b>3</b>, <b>5</b>, and <b>18</b>) and three graminin-like compounds, fusofuranones A-C (<b>19</b>-<b>21</b>), together with 14 known naphthoquinone derivatives, were isolated from the solid fermentation of <i>Fusarium solani</i>, an endophytic fungus obtained from medicinal plant as tea, <i>Camellia chrysantha</i>. The structures of new compounds were elucidated based on chemical evidence and spectral data analysis (1D and 2D-NMR, HR-ESI-MS, ECD, SC-XRD). Among the isolated compounds tested, 2-acetonyl-3-methyl-5-hydroxy-7-methoxy-naphthazarin (<b>11</b>) exhibited the most potent inhibitory activity against pancreatic cancer in PANC-1, MiaPaCa-2, and BxPC-3 cells. Network pharmacology analysis revealed that compound <b>11</b> inhibited cell proliferation and promotion of apoptosis by targeting epidermal growth factor receptor (EGFR), which were confirmed by cellular thermal shift assay (CETSA), microscale thermophoresis (MST) and EGFR stably knockdown cells model assay, respectively. In addition, molecular mechanism studies <i>in vitro</i> showed that <b>11</b> could suppress the growth of pancreatic cancer cells by targeting EGFR and effectively inhibit downstream PI3K/Akt signaling pathway. Collectively, these findings provide a new EGFR targeting natural product for the treatment of pancreatic cancer.