Ferritin consists of heavy (FTH1) and light (FTL) chains, and the expression of each subunit is associated with cancer risk, although this association varies by cancer type. In this study, we aimed to investigate the mechanism underlying ferritin involved in KRAS-mutated pancreatic ductal adenocarcinoma (PDAC) progression and metabolism reprogramming. We revealed that high FTH1 expression is associated with KRAS-mutant pancreatic cancer, where knockdown of FTH1 reduced SUIT-2 and Mia PaCa-2 PDAC cell viability and colony forming ability in vitro and xenograft tumor growth in vivo . Metabolomics analysis has shown that proline metabolism is significantly altered in SUIT-2 cells after FTH1 knockdown, which we further found that FTH1 is positively correlated with the level of pyrroline-5-carboxylate reductase 1 (PYCR1), but not proline dehydrogenase (PRODH), and its cross-talk contributes to KRAS-mutated PDAC cell progression. Our study, therefore, suggests that FTH1 and its cross-talk with PYCR1 may be a potential target for pancreatic cancer research and developing related metabolite-based therapeutic strategies are needed to improve the prognosis of PDAC patients.
