Enhanced cytokine signaling and ferroptosis defense interplay initiates obesity-associated pancreatic ductal adenocarcinoma.

Obesity is a significant risk factor for various cancers, including pancreatic cancer (PC), but the underlying mechanisms are still unclear. In our study, pancreatic ductal epithelial cells were cultured using serum from human subjects with diverse metabolic statuses, revealing that serum from patients with obesity alters inflammatory cytokine signaling and ferroptosis, where a mutual enhancement between interleukin 34 (IL-34) expression and ferroptosis defense was observed in these cells. Notably, oncogenic KRAS G12D amplified their interaction and this leads to the initiation of pancreatic ductal adenocarcinoma (PDAC) in diet-induced obese mice via macrophage-mediated immunosuppression. Single-cell RNA sequencing (scRNA-seq) of human samples showed that cytokine signaling, ferroptosis defense, and immunosuppression are correlated with the patients' body mass index (BMI) during PDAC progression. Our findings provide a mechanistic link between obesity, inflammation, ferroptosis defense, and pancreatic cancer, suggesting novel therapeutic targets for the prevention and treatment of obesity-associated PDAC.