Isolinderalactone suppresses pancreatic ductal adenocarcinoma by activating p38 MAPK to promote DDIT3 expression and trigger endoplasmic reticulum stress.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, and its incidence rate is increasing. PDAC patients are prone to acquired chemotherapy resistance, necessitating the development of novel drugs to provide alternative treatment options. In recent years, traditional folk medicine and its active ingredients have garnered increasing attention for their effectiveness in treating tumors. Here, we discovered that isolinderalactone (ILL), a sesquiterpenoid compound extracted from the traditional Chinese medicine Lindera aggregata (Sims) Kosterm., possesses anti-PDAC pharmacological activity. Our results revealed that ILL decreased the proliferative capacity of PDAC cells in a time- and dose-dependent manner. The migration and invasion abilities of tumor cells were significantly suppressed due to the inhibition of epithelial-to-mesenchymal transition (EMT). Additionally, the cell cycle was arrested in the G2/M phase, leading to apoptosis, and inhibiting inflammatory responses. Mechanistically, bioinformatics analysis of molecular expression changes combined with in vivo and in vitro experiments demonstrated that ILL induces persistent ER stress by activating p38 MAPK signaling pathway, thus promoting the expression of DDIT3, and ultimately suppressing progression-related cell behaviors. Animal experiments confirmed that ILL also inhibited PDAC development in vivo with minimal toxicity. In summary, our study identified ILL as a potential therapeutic compound for PDAC treatment.