Using pancreatic ductal adenocarcinoma cells, we show that excessive copper triggers a proteotoxic stress response (PSR), activating HSF1 and that overexpressing HSF1 diminishes intracellular copper accumulation and prevents excessive copper-induced cell death and amyloid fibrils formation, highlighting HSF1′s role in preserving proteasomal integrity. The gene discussed is HSF1; the disease is pancreatic ductal adenocarcinoma.