Activated Stellate Cell Paracrine HGF Exacerbated Pancreatic Cancer Cell Ferroptosis Resistance

As a refractory tumor, pancreatic carcinoma is more vulnerable to ferroptosis, a novel regulated cell death mode. However, the exact role of pancreatic stellate cells (PSCs) in pancreatic cancer ferroptosis is still unclear. Using the coculture system, we revealed that activated PSCs promote pancreatic cancer cell ferroptosis resistance. Mechanistically, activated PSCs secreted HGF, which further activated the HGF receptor, c-MET, in pancreatic cancer cells, prevented lipid peroxidation, and ultimately triggered pancreatic cancer cell ferroptosis resistance in vitro and in vivo. TCGA and GEPIA databases also revealed a strong correlation between c-MET and antiferroptosis indicators. Our study supplied the evidence for the cross-talk between activated PSCs and pancreatic cancer cells in ferroptosis, which suggested a strategy to inhibit PSC paracrine signaling for preventing pancreatic carcinoma ferroptosis resistance.