Securinine suppresses pancreatic cancer progression by activating the p38 MAPK pathway to upregulate CHOP and induce endoplasmic reticulum stress.

Pancreatic cancer (PC) remains among the most lethal gastrointestinal malignancies and is characterized by poor prognosis and limited therapeutic options. The discovery of natural antitumor compounds from traditional Chinese medicine has emerged as a promising research direction. Securinine (SCR), the main alkaloid from Securinega suffruticosa, has shown antitumor potential in various models, although its mechanism in PC requires further elucidation. This study investigated the inhibitory effects of SCR on human PC cells, focusing on its role in activating the p38 MAPK pathway and inducing CHOP expression to trigger endoplasmic reticulum stress. Using CCK-8, colony formation, and EdU assays, we found that SCR significantly suppressed PC cell proliferation in a time- and concentration-dependent manner. Wound healing and Transwell assays demonstrated impaired migration and invasion capabilities, whereas flow cytometry revealed G1 phase cell cycle arrest and increased apoptosis. Transcriptome sequencing and bioinformatics analysis revealed p38 MAPK as a key pathway, a finding that was confirmed by Western blotting, which revealed that SCR induced the phosphorylation of p38 and the upregulation of CHOP. Both p38 inhibition and CHOP siRNA interference markedly reversed the antitumor effects of SCR. In a xenograft mouse model, SCR effectively inhibited tumor growth without observable systemic toxicity. Our findings indicate that SCR suppresses pancreatic cancer progression through the p38 MAPK/CHOP axis and endoplasmic reticulum stress induction, providing experimental evidence for the potential of SCR as a therapeutic agent against PC.