Diabetic Ferroptosis and Pancreatic Cancer: Foe or Friend?

Significance: Pancreatic cancer and diabetes have a reciprocal causation relationship. As a potential risk factor, diabetes increases morbidity and promotes pancreatic cancer progression. The main mechanisms include islet dysfunction-induced systemic metabolic disorder, pancreatic stellate cell activation, and immunosuppression. Ferroptosis is regarded as regulated cell death, which participates in chemotherapy resistance and is refractory to radiation therapy and immunotherapy. Diabetes-induced ferroptosis causes many complications, but the underlying mechanism of diabetes-related ferroptosis in pancreatic cancer has not been discussed. Recent Advances: Ferroptosis alleviates pancreatic intraepithelial neoplasia (PanIN) progression by activating chronic inflammation. The specific drugs that cause ferroptosis achieve tumor suppression by inducing lipid peroxidation. Ferroptosis plays pro and con roles in cancer. Both the ferroptosis inhibitor and inducer exhibit antitumor effects through killing cancer cells or directly affecting tumor growth. Diabetes-induced ferroptosis contributes to tumor cell death by different components, including tumor cells, fibroblasts, immune cells, and adipocytes. A better understanding of its role in modulating the tumor microenvironment will reveal diabetes-associated ferroptotic features in cancer development, which can be used to figure out possible treatment strategies for cancer patients with hyperglycemia. Critical Issues: We demonstrate the potential roles of diabetes-related ferroptosis in pancreatic cancer progression and discuss ferroptosis-related antitumor effects and therapeutics for pancreatic cancer treatment. Future Directions: Further studies are required to highlight mechanisms of diabetes-mediated ferroptosis in pancreatic cancer tumorigenesis and progression. The antitumor effects of ferroptosis regulators combined with chemotherapy, targeted therapy, or immunotherapy in diabetic patients should be investigated. We hope that pancreatic cancer patients with diabetes will benefit from ferroptosis-related therapies. Antioxid. Redox Signal. 37, 1206-1221.