Abstract

Iron (Fe) is a crucial metal and plays a vital role in a variety of cellular processes. Studies in mammals have indicated that transferrin (TF) and transferrin receptor (TfR), jointly iron ion transport, while also contributing to antibacterial immunity. However, systematic reports on the functions and regulatory mechanisms of these components in teleost fish are lacking. In this study, TF protein was purified and identified from the serum of Nile tilapia ( Oreochromis niloticus ). A range of experimental techniques was employed to demonstrate that OnTF can inhibit the proliferation of pathogenic bacteria both in vivo and in vitro . Meanwhile, OnTF interacts with the OnTfR1 receptor on the cell surface, facilitating phagocytosis and bacterial clearance, thereby providing immune protection to the organism. Notably, OnTfR1 directly influences the secretion of OnHepc through the BMP-SMAD signaling pathway. The increased mortality of tilapia caused by downregulated OnTfR1 expression during pathogenic bacterial infection can be effectively alleviated by supplementing (r)Hepc protein. Moreover, OnTfR1 also played an indispensable role in maintaining the stability of the fish intestinal microecology and resisting pathogen infections. Overall, this study represents the first systematic investigation into the functional roles of molecules involving in iron homeostasis regulation in teleost fish. It elucidates that the OnTF-TfR1 axis, as a core pathway for iron ion uptake and metabolic regulation, plays a significant role in resisting pathogen infections and maintaining the stability of the intestinal microbiota. These findings provide new insights into understanding the functional association between iron metabolism and innate immune defense during adaptive evolution.