A synthetic 6-O-sulfated glycopolymer induces tissue iron accumulation via competitively inhibiting the hepcidin/FPN1 axis

Highly sulfated heparin-like glycosaminoglycans (GAGs) have been closely linked to disrupted iron homeostasis, yet no studies have employed site-specific sulfation modifications of GAGs to develop macromolecular compounds capable of modulating iron metabolism. Based on preliminary research, our team designed and synthesized an glycopolymer with 6-O-sulfated GlcNAc. In vitro administration experiments demonstrated that 6-O-sulfated glycopolymer significantly inhibits hepcidin-mediated internalization and degradation of ferroportin 1 (FPN1) on macrophage membranes, reducing cellular iron storage— an effect superior to that of conventional HS. Following CY5-labeled 6-O-sulfated glycopolymer administration in vivo , fluorescence tracking revealed broad tissue distribution, including abdominal organs and cortical bone. Meanwhile, 6-O-sulfated glycopolymer markedly decreased serum hepcidin level, increased serum ferritin concentration, and induced significant iron accumulation in the liver and bone cortex, while results from HE staining of hepatic, splenic, and renal tissues confirmed its biological safety. Computational docking, surface plasmon resonance (SPR) assay, and cellular thermal shift assay-western blot (CETSA-WB) further demonstrated high-affinity binding between 6-O-sulfated glycopolymer and hepcidin. These findings establish the 6-O-sulfate group as the critical functional moiety in HS-mediated systemic iron regulation, where 6-O-sulfated glycopolymer competitively inhibits the hepcidin/FPN1 axis to activate macrophage iron efflux, ultimately promoting tissue iron accumulation.