BACKGROUND: Pancreatic cancer is a highly aggressive malignancy with limited therapeutic options and poor prognosis. Erianin, a natural product, has shown anti-cancer properties in various malignancies, but its effects on pancreatic cancer and the underlying mechanisms remain poorly understood. AIM: This study aimed to evaluate the anti-tumor effects of erianin on pancreatic cancer cells and to explore the regulatory mechanisms involved. METHODS: PANC-1 and ASPC-1 pancreatic cancer cells were treated with erianin at different concentrations. Cell viability and proliferation were assessed using the Cell Counting Kit-8 (CCK-8) assay and colony formation assay. Cell cycle distribution was analyzed by flow cytometry. Ferroptosis was evaluated by measuring levels of Fe²⁺, total iron, and lipid reactive oxygen species (ROS). Western blotting was used to detect the expression of cell cycle regulators and ferroptosis-related proteins. RESULTS: Erianin significantly suppressed pancreatic cancer cell viability and proliferation in a dose-dependent manner. It induced G0/G1 phase arrest, accompanied by downregulation of cyclin D1 and cyclin A. Furthermore, erianin promoted ferroptosis, as evidenced by increased Fe²⁺, total iron, and lipid ROS levels, along with reduced glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression. The ferroptosis inhibitor Ferrostatin-1 reversed these effects, validating ferroptosis as a critical mechanism in erianin's anti-cancer activity. CONCLUSION: Erianin exerts potent anti-tumor effects on pancreatic cancer cells by inducing cell cycle arrest and ferroptosis. These findings establish erianin as a promising therapeutic candidate for pancreatic cancer treatment.