Cervical cancer is the second most prevalent malignancy in female reproductive system and a major cause of morbidity and mortality worldwide. Its proliferation and migration are closely associated with cellular zinc (Zn²⁺), which is meticulously regulated by the human Zn²⁺ importers (Zrt-/Irt-like proteins, hZIPs) and exporters (zinc transporter, hZnTs). Among them, hZnT1, the only Zn²⁺ transporter located on the cell membrane, exports Zn²⁺ from the cytosol to extracellular milieu and is significantly up-regulated in cervical cancer cells. Hence, deciphering the physiological function of hZnT1 and developing therapeutic agents that specifically target this transporter could be an effective strategy for cervical cancer treatment.
Recently, researchers Wang Yaxin and Ye Sheng from Tianjin University determined the cryo-EM structure of hZnT1 and identified the critical residues involved in Zn²⁺ transport. Based on this structure, they performed virtual screening and found that Bardoxolone methyl (CDDO Methyl Ester, CDDO-ME) potently inhibits Zn²⁺ transport mediated by hZnT1. The cellular and animal experiments demonstrated that CDDO-ME specifically targets hZnT1, effectively suppressing the proliferation and migration of cervical tumors, with low toxicity and excellent biosafety.
To further elucidate the molecular mechanism by which CDDO-ME inhibits hZnT1, the researchers conducted a detailed analysis of the hZnT1-CDDO-ME complex structure with an overall resolution of 3.78 A. Combined with molecular dynamics simulations, they found that CDDO-ME can precisely bind above the Zn²⁺ binding site in the transmembrane region of hZnT1, and that TM2 exerts spatial hindrance to CDDO-ME during the conformational transition, effectively preventing Zn²⁺ efflux. This discovery not only reveals the mechanism of action of CDDO-ME but also provides a crucial structural basis for designing more effective drugs (Figure 1).

This study presents, for the first time, definitive experimental evidences demonstrating a close relationship between hZnT1 and the proliferation and migration of cervical cancer cells.
DOI:10.1093/procel/pwaf044