Paraptosis: A methuosis-distinct vacuolar cell death

Paraptosis is a non-apoptotic form of cell death characterized primarily by extensive cytoplasmic vacuolation from swollen endoplasmic reticulum (ER) and/or mitochondria. Current evidence supports a relatively consistent morphological phenotype, whereas the underlying molecular mechanisms appear heterogeneous and context-dependent. Recurrent molecular associations reported in paraptosis models include mitogen-activated protein kinase (MAPK) activation, ER stress, proteostasis disruption, reactive oxygen species (ROS) accumulation, calcium imbalance, and, in some settings, protein synthesis dependence. A major focus is distinguishing paraptosis from methuosis, highlighting differences in vacuole origin, molecular pathways, and inhibitors. We also summarize a stepwise identification framework, from morphology to biochemical validation. Besides, paraptosis induction as a therapeutic strategy is briefly discussed in cancer therapy. By integrating current evidence, this work provides a clear reference for studying paraptosis as a distinct cell death process.