Pancreatic cancer is an aggressive malignancy with poor prognosis and frequent resistance to standard anticancer therapies, highlighting the need for treatments that more effectively induce tumor cell death. Here, we aimed to identify a drug candidate that triggers cell death and to uncover its molecular mechanism in pancreatic cancer. We performed high-throughput screening using a library of 2,051 FDA-approved compounds in pancreatic cancer cells and used cell viability assays to identify agents that induce cell death. The antitumor effects of the lead compound were characterized by transmission electron microscopy, mCherry-EGFP-LC3B, lipid peroxidation and mitochondrial function assays, and an orthotopic LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) mouse model. Single-cell RNA sequencing, surface plasmon resonance (SPR), co-immunoprecipitation, and western blotting were used to elucidate the underlying mechanism. High-throughput screening identified the antiarrhythmic agent dronedarone as a compound that significantly inhibited pancreatic cancer cell growth and can exert effective antitumor effects in vivo. Single-cell RNA sequencing and pharmacologic rescue experiments indicated that ferroptosis is a major form of dronedarone-induced regulated cell death in pancreatic cancer cells. Mechanistically, dronedarone directly bound to glutathione peroxidase 4 (GPX4), inhibited its enzymatic activity, and promoted p62-mediated autophagic degradation of GPX4, leading to mitochondrial lipid peroxidation and GPX4-dependent ferroptosis. Moreover, the ferroptosis inhibitor ferrostatin-1 attenuated dronedarone-induced lipid peroxidation, preserved GPX4 expression, and partially reversed its antitumor effects in the orthotopic KPC mouse model. Dronedarone serves as an unrecognized promoter of ferroptosis in pancreatic cancer by targeting p62-mediated autophagic degradation and functional inactivation of GPX4, providing a mechanistic and translational rationale for exploiting ferroptosis in pancreatic cancer.
Gu et al. (Sat,) studied this question.