Targeting CYBA inhibits hepatic metastasis of pancreatic cancer through AKT/MLC2 pathway

Pancreatic cancer is known as the "king of cancers", mainly due to its aggressive metastatic potential and significant heterogeneity. The liver represents the most frequent site of distant metastasis in pancreatic ductal adenocarcinoma (PDAC). Currently, effective treatment options remain critically limited for patients diagnosed with PDAC-derived hepatic metastases. In our research, we integrated single-cell transcriptomic data from multiple samples to delve into the heterogeneity of epithelial cells. We identified a subtype of malignant metastatic epithelial cells and identified CYBA, which encodes the p22^phox protein, as a key molecular target promoting hepatic metastasis in PDAC. Through experimental validation, we confirmed that p22^phox was highly expressed in pancreatic cancer samples with hepatic metastasis, and its knockdown inhibited the migration of pancreatic cancer cells and metastasis to the liver. Mechanistically, p22^phox activated the PI3K-AKT signaling pathway and increased MLC2 phosphorylation, facilitating the polymerization of motor proteins in pancreatic cancer cells and promoting tumor metastasis. NOX inhibitors were found to suppress PI3K-AKT and p-MLC2 pathways, as well as inhibit the migration of pancreatic cancer cells and metastasis to the liver. Therefore, targeting the activity of p22^phox in pancreatic cancer may emerge as an effective therapeutic strategy for treating hepatic metastasis in PDAC patients.