In Pancreatic cancer stem cells (PaCSC), ISG15 and ISGylation are required for mitophagy and metabolic plasticity, loss of ISG15 lead to increased accumulation of dysfunctional mitochondria, reduced OXPHOS and impaired mitophagy and finally negatively impacts PaCSC stemness 189. Here, ISG15 is linked to familial pancreatic carcinoma.