Paraptosis Turning Cellular Stress into Therapeutic Weapon for Urological Diseases

Drug resistance and impaired apoptosis limit durable responses in urological malignancies. Paraptosis is a regulated, nonapoptotic cell death program marked by prominent cytoplasmic vacuolization, typically driven by endoplasmic reticulum (ER) swelling and mitochondrial dysfunction. This perspective synthesizes emerging evidence in prostate, bladder, and renal cancers and proposes a stress-axis framework in which diverse inducers converge into 3 mechanistic classes: (a) proteostasis disruptors that precipitate acute ER stress, (b) ion-handling modulators that trigger lethal mitochondrial Ca²⁺ overload, and (c) redox regulators that amplify reactive-oxygen-species-driven proteotoxic stress. We discuss how natural products, repurposed agents, and delivery platforms can be integrated with chemotherapy, targeted therapy, or immunotherapy to overcome resistance and exploit death-pathway cross talk. Key translational priorities include defining pathway-specific biomarkers, mapping ER-mitochondrion signaling thresholds, and dissecting stress-buffering and cytoprotective autophagy as resistance mechanisms. Clarifying these principles may enable the context-specific exploitation of paraptosis across urological cancers and related diseases, in both primary and therapy-refractory settings.