Targeting PKCa alleviates iron overload in diabetes and hemochromatosis through the inhibition of ferroportin

• PKCa is novel and positive regulator of ferroportin by modulating the trafficking and localization of Fpn

• Inhibition of PKCa reduces body iron content in physiology, diabetes, and hereditary hemochromatosis

Ferroportin (Fpn) is the only iron exporter, playing a crucial role in systemic iron homeostasis. Fpn is negatively regulated by its ligand hepcidin, but other potential regulators in physiological and disease conditions remain poorly understood. Diabetes is a metabolic disorder that develops body iron loading with unknown mechanisms. By utilizing diabetic mouse models and human duodenal specimens, we demonstrated that intestinal Fpn expression was increased in diabetes in a hepcidin-independent manner. Protein kinase C (PKC) is hyperactivated in diabetes. We showed that PKC was required to sustain baseline Fpn expression and diabetes induced Fpn upregulation in the enterocytes and macrophages. Knockout of PKC abolished diabetes associated iron overload. Mechanistically, activation of PKC increased the exocytotic while decreased the endocytic trafficking of Fpn in the resting state. Hyperactive PKC also suppressed hepcidin-induced ubiquitination, internalization, and degradation of Fpn. We further observed that iron loading in the enterocytes and macrophages activated PKC, acting as a novel mechanism to enhance Fpn-dependent iron efflux. Finally, we demonstrated that the loss-of-function of PKC and pharmacological inhibition of PKC significantly alleviated hereditary hemochromatosis associated iron overload. Our study has highlighted, for the first time, that PKC is an important positive regulator of Fpn and a new target in the control of iron homeostasis.