Role of paraptosis in cancer: Molecular mechanisms and therapeutic potentials

Paraptosis represents a mode of cell death, which is separate from classical apoptosis. Classical apoptotic pathways are caspase-dependent, accompanied by cell shrinkage, chromatin condensation, and apoptotic body formation. In contrast, paraptosis is characterized by cytoplasmic vacuolization without typical apoptotic nuclear alterations, and its signaling operates independently of the caspase system. Unlike apoptosis, paraptosis primarily depends on the mitogen-activated protein kinase (MAPK) signaling pathway for its mediation, highlighting its unique regulatory framework separate from classical apoptotic pathways. Since it does not overlap with apoptotic resistance mechanisms, inducing paraptosis holds great potential to overcome resistance to conventional chemotherapy and radiotherapy. Therefore, inducing paraptosis in cancer cells has crucial potential value for current cancer treatment. This article thoroughly explores the regulatory mechanisms of paraptosis and synthesizes its dual functions in the progression of cancer cells. Additionally, we discuss in detail cancer treatment strategies based on targeting paraptosis and analyze the feasibility and potential advantages of combining paraptosis with other cell death forms and various therapeutic methods to enhance cancer treatment efficacy.