Cetylpyridinium chloride triggers paraptosis to suppress pancreatic tumor growth via the ERN1-MAP3K5-p38 pathway

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid malignancy with low 5-year survival and limited treatment options. We conducted an unbiased screening using FDA-approved drug and demonstrated that cetylpyridinium chloride (CPC), a component commonly found in mouthwash and known for its robust bactericidal and antifungal attributes, exhibits anticancer activity against human PDAC cells. CPC inhibited PDAC cell growth and proliferation by inducing paraptosis, rather than apoptosis. Mechanistically, CPC induced paraptosis through the initiation of endoplasmic reticulum stress, leading to the accumulation of misfolded proteins. Subsequently, the endoplasmic reticulum stress to nucleus signaling 1 (ERN1)-mitogen-activated protein kinase kinase kinase 5 (MAP3K5)-p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated, ultimately culminating in the induction of paraptosis.