Fe 2+ Triggers Endocytosis of Carrier Proteins in Mammalian Cells

作者：Weibo Zhang, Chong Chen, Ran Wang, Yixuan Li, Yinhua Zhu, Jiazeng Sun, Yongting Luo, Junjie Luo, Liang Zhao, Yanan Sun, Huiyuan Guo, Hao Zhang, Bing Fang, Yao Hu, Rong Liu, Xiaoyu Wang, Jiayue Guo, Ping Liu, Peng An, Pengjie Wang, Juan Chen, Fazheng Ren · 发表于：Advanced Healthcare Materials · 年份：2025 · DOI：10.1002/adhm.202502090 · 被引用次数：1 · 研究领域：Erythrocyte Function and Pathophysiology、Lipid Membrane Structure and Behavior、Cellular transport and secretion

Abstract Human serum albumin (HSA) plays an indispensable role as a carrier of endogenous and exogenous substances in vivo. The efficiency of endocytosis determines the transport capacity. However, the potential for enhancing the efficiency of HSA endocytosis remains largely unknown. This research represented a substantial advancement, revealing that Fe 2+ markedly increased HSA endocytosis. Moreover, Fe 2+ facilitated the endocytosis and transport of HSA in vivo. The enhancement in HSA uptake facilitated by Fe 2+ is markedly decreased following iron chelation, indicating a specific interaction between Fe 2 ⁺ and HSA that promoted endocytosis. Moreover, the study elucidated that FcRn and caveolin regulated HSA endocytosis under normal conditions. Yet, in the presence of Fe 2 ⁺, endocytosis shifted toward clathrin‐ and caveolin‐enriched membrane domains, requiring both divalent metal transporter 1 (DMT1) and FcRn for efficient process completion. Thereby a new pathway is discovered for Fe 2+ ‐dependent HSA endocytosis involving DMT1 and clathrin. This findings highlighted the crucial role of iron in enhancing HSA endocytosis and transport, establishing Fe 2+ as a vital endocytic enhancer that required binding to HSA to substantially improve its uptake. This insight into the mechanism of HSA endocytosis not only expands the understanding of protein transport but also opens new avenues for therapeutic intervention.