As an essential trace element, zinc is crucial for the development and function in mammals. It is estimated that over 10 % of the proteins in the human proteome are capable of binding zinc (Andreini et al., 2006, Kambe et al., 2017, MacKenzie and Bergdahl, 2022). As a co-factor or component of more than 300 metalloenzymes, it is utilized for catalyzing reactions or stabilizing protein structures (Lee et al., 2018, Smidt and Rungby, 2012). Accumulating evidence indicates that abnormal zinc homeostasis is involved in a variety of diseases including cancer (Thingholm et al., 2020, Wang et al., 2020), metabolic diseases (Li et al., 2017, Mitchell et al., 2023, Weijers, 2010), neurodegenerative disorders and immune system disorders (John et al., 2010, Kuliyev et al., 2021, McAllister and Dyck, 2017). Zinc is present in cells as a divalent cation (Zn2+) and cannot cross the cellular membrane through diffusion (Ogawa et al., 2018). Rather, the free cellular Zn2+ level is mainly regulated by two solute carrier (SLC) families of zinc transporters (SLC30 and SLC39) and a group of zinc-binding proteins called metallothioneins (Pomorski et al., 2023, Singh et al., 2023). Metallothioneins are small Cys-rich proteins and are expressed ubiquitously in human (Pavić et al., 2019, Wang et al., 2023). They play a crucial role in buffering the intracellular Zn2+, thereby controlling the availability of Zn2+ to other proteins and cellular processes, and have been reviewed elsewhere (Blindauer and Leszczyszyn, 2010, Coyle et al., 2002, Krizkova et al., 2018). On the other hand, the movement of Zn2+ between the cytosol and the extracellular (or luminal) compartments is primarily mediated by SLC30 and SLC39 families, which are the focus of the current review.

The SLC30 transporters are known as ZnTs, which belong to the cation diffusion facilitator (CDF) superfamily (Cotrim et al., 2019, Huang and Tepaamorndech, 2013, Kambe et al., 2021), whereas the SLC39 proteins are called ZIPs (Zrt and Irt-like proteins) (Jeong and Eide, 2013). ZnTs control the egress of Zn2+ from the cytoplasm, preventing the cytotoxicity caused by excessive cellular Zn2+, while the ZIP family regulates the inflow of Zn2+ into the cytoplasm to remedy Zn2+ deficiency (Giacconi et al., 2018, Kambe et al., 2015). To date, ten ZnTs (ZnT1 to ZnT10) and 14 ZIPs (ZIP1 to ZIP14) have been identified in human (Eide, 2006, Hu, 2021, Kambe et al., 2014, Kambe et al., 2015, Ogawa et al., 2018). Recently, TMEM163 has been proposed to be a new member of the ZnT family (Escobar et al., 2022, Sanchez et al., 2019, Styrpejko and Cuajungco, 2021). Based on protein sequence similarities, both the ZnT and ZIP families can be divided into four subfamilies (Bowers and Srai, 2018, Chen et al., 2024, Cotrim et al., 2019, Huang and Tepaamorndech, 2013, Jeong and Eide, 2013, Kambe et al., 2021, Liu et al., 2025, Yin et al., 2023) (Fig. 1a). For ZnTs, ZnT5 and ZnT7 are in subfamily I; ZnT2, ZnT3, ZnT4 and ZnT8 are grouped in subfamily II; subfamily III contains ZnT1 and ZnT10, and subfamily IV contains ZnT6 and ZnT9 (Chen et al., 2024, Cotrim et al., 2019, Huang and Tepaamorndech, 2013, Kambe et al., 2021, Liu et al., 2025, Yin et al., 2023). The ZIP family is divided into subfamilies I, II, gufA, and LIV-1. ZIP9 belongs to the ZIP I subfamily; ZIP1, ZIP2, and ZIP3 are grouped in the ZIP II subfamily; ZIP11 is in the gufA subfamily, and the remaining 9 ZIPs are classified as the LIV-1 subfamily members (Bin et al., 2018, Chen et al., 2024, Jeong and Eide, 2013, Kambe et al., 2021, Liu et al., 2025, Yin et al., 2023). Different ZnT and ZIP members are localized to specific cellular locations to fulfill their functions (Fig. 1b). In the ZnT family, ZnT1 is mainly expressed on the plasma membrane, while the other ZnTs are localized to the membrane of different organelles, including secretory/synaptic vesicles, endosomes, the Golgi apparatus, the endoplasmic reticulum (ER), the nucleus and mitochondria (Kowalczyk et al., 2021, Levaot and Hershfinkel, 2018, Ma et al., 2022). Meanwhile, the ZIP family members are mostly localized to the plasma membrane, whereas ZIP7, ZIP8, ZIP9 and ZIP13 have also been shown on the intracellular compartments including ER, the Golgi apparatus and lysosomes (Kambe et al., 2017).

The first mammalian ZnT (ZnT1) was cloned in 1995 by selecting Zn2+-resistant baby hamster kidney cells (Palmiter and Findley, 1995), but high-resolution structures of eukaryotic ZnTs were not available until recently (Bui et al., 2023, Ishida et al., 2024, Li et al., 2024a, Long et al., 2024, Sun et al., 2024a, Xue et al., 2020, Zhang et al., 2023a). In the meantime, a bacterial ZnT homolog, YiiP, has proven to be a valuable model for studying the structure and transport mechanism of ZnTs (Coudray et al., 2013, Gupta et al., 2014, Hussein et al., 2023, Lopez-Redondo et al., 2021, Lopez-Redondo et al., 2018, Lu and Fu, 2007, Lu et al., 2009, Sharma and Merz, 2022). Combined with functional assays and molecular dynamics simulations, structures of ZnTs have revealed mechanistic insight into the Zn2+ transport in the ZnT family (Bui et al., 2023, Daniels et al., 2020, Golan et al., 2018, Ishida et al., 2024, Li et al., 2024a, Long et al., 2024, Sun et al., 2024a, Xue et al., 2020, Zhang et al., 2023a) (Table 1). On the other hand, the ZIP family was named after the iron-regulated transporter 1 (Irt1) of Arabidopsis thaliana and the zinc-regulated transporter 1/2 (Zrt1 and Zrt2) of Saccharomyces cerevisiae, which are the first ZIP members being characterized (Eide et al., 1996, Zhao and Eide, 1996a, Zhao and Eide, 1996b). The first ZIP structure was solved for the extracellular domain of a mammalian ZIP4 in 2016 (Zhang et al., 2016). Since then, more structural advancements have been achieved using a bacterial ZIP homolog from Bordetella bronchiseptica (BbZIP), revealing a binuclear metal binding center and an elevator-type mechanism of Zn2+ transport in the ZIP family (Pang et al., 2023, Wiuf et al., 2022, Zhang et al., 2020, Zhang et al., 2017, Zhang et al., 2024, Zhang et al., 2023b) (Table 2). Previous reviews have summarized ZnT transporter structures determined by X-ray crystallography and cryo-EM studies (Bui and Inaba, 2024), including YiiP, ZnT7, and ZnT8. In this review, we have also incorporated recent structural advances on ZnT1, ZnT3 and ZnT4 to provide a more comprehensive view on the conformational states and transport mechanisms of ZnTs.