Dipeptidyl Peptidase-4 modulates Long-chain Acyl-CoA synthetase 4 to Promote Lipid Peroxidation and Regulate Ferroptosis in Pancreatic Cancer

Abstract Background: The global mortality rate of pancreatic ductal adenocarcinoma (PDAC) is one of the highest among all cancers, and curative chemotherapeutics are essentially nonexistent. Dipeptidyl peptidase-4 (DPP4) plays a critical role in ferroptosis, a recently discovered regulated mechanism of necrotic cell death that has an important function in colorectal cancer. However, whether DPP4 contributes to ferroptosis in pancreatic cancer has remained unknown. Methods: DPP4 expression status was evaluated in PDAC tissues using tissue chip immunohistochemistry. The effects of DPP4 re-expression on cell proliferation, the cell cycle and energy metabolism were determined. DPP4-related cancer pathways was identified by RNA-seq analyses. The clinical impact of DPP4 in driving ferroptosis and attenuating gemcitabine sensitivity was assessed in DPP4 knockout (KD) mice orthotopic xenograft models of PDAC.Results: We found that DPP4 is expressed at low levels in PDAC, and that it significantly inhibited cell proliferation by causing G1–S cell cycle arrest, inhibiting energy metabolism, and promoting erastin-induced ferroptosis in vitro; it also suppressed tumor growth in transgenic orthotopic xenograft mouse models (P < 0.001). Importantly, the sensitivity of cells overexpressing DPP4 to gemcitabine and ferroptosis was respectively decreased and increased. Mechanistically, DPP4 facilitated ferroptosis by binding long-chain acyl-CoA synthetase 4 (ACSL4), and interaction with DPP4 stabilized ACSL4 by inhibiting its ubiquitin-mediated degradation and subsequent lipid peroxidation. Conclusions: These findings identify a novel role of DPP4 in ferroptosis and suggest a potential therapeutic strategy with which to overcome gemcitabine resistance in PDAC.