Maize gets an iron boost: Biofortification breakthrough holds promise to combat iron deficiency

This commentary describes recent research discovering that the NAC transcription factor gene ZmNAC78 controls iron intake in maize and its implications for biofortification of this important crop. Using ZmNAC78, iron levels in maize can be more than doubled compared with current varieties. Micronutrient deficiencies affect more than two billion people worldwide, resulting in poor health, developmental issues, and even death. Iron deficiency is one of the most prevalent micronutrient deficiencies worldwide and impacts approximately one-third of the global population. It can lead to anemia, fatigue, poor pregnancy outcomes, and impaired cognitive development in children (Black et al., 2013). Maize (corn) is a dietary staple for millions of people living in sub-Saharan Africa, but the amount of iron in edible kernels is naturally low. Survey data revealed a 20.1% prevalence of anemia among Chinese residents, half of whom specifically suffer from iron deficiency anemia (Yu et al., 2021). While iron supplements exist, their high-cost limits accessibility. Increasing the iron content of staple crops such as maize offers a more cost-effective and sustainable approach to improving iron nutrition for large populations, especially in developing countries where maize is a dietary mainstay (Kawakami and Bhullar, 2018; Kong et al., 2022). Little is known regarding the genetics and transport mechanisms facilitating iron loading specifically into maize grains. Identifying genes regulating this process represents an important breakthrough, as iron localization within seeds has remained an elusive bottleneck for biofortification efforts. In a recently published article in Science, Yan et al. uncovered novel insights for the first time regarding the genetics underlying iron loading in maize kernels (Figure 1) (Yan et al., 2023). The researchers first assessed a diverse panel of 273 maize lines, identifying wide variation in kernel iron levels. They subsequently performed a genome-wide association study (GWAS), allowing them to correlate genomic markers with phenotypic traits. Through genetic analysis, researchers identified 11 genetic markers significantly linked to iron concentration in maize kernels. To identify the genes controlling this iron content, they analyzed gene expression activity in different maize lines with varying iron levels. Only one gene, ZmNAC78, exhibited consistently higher activity in the lines with high iron levels. This finding suggested that the NAC transcription factor ZmNAC78 (NAM/ATAF/CUC DOMAIN TRANSCRIPTION FACTOR 78) acts as a regulator of iron content. Investigating natural promoter variants affecting ZmNAC78 expression, they found that different variants of the ZmNAC78 promoter correlate with differential expression of the gene in maize endosperm tissue, which in turn impacts iron concentrations in the kernels (Yan et al., 2023). Further investigation revealed that ZmNAC78 directly upregulates iron transporter genes, enabling increased loading of iron into developing maize kernels (Yan et al., 2023). Furthermore, to investigate the potential use of ZmNAC78 in breeding, researchers have employed this polymorphism in the ZmNAC78 core promoter sequence and categorized corn into haplotype-1, which is characterized by a high grain iron content, and haplotype-2, which is characterized by a low grain iron content. The development of molecular markers allows them to rapidly integrate "high-iron" alleles into breeding lines. NAC78: A master regulator of iron biofortification in maize kernels ZmNAC78 acts as a master regulator of iron loading in maize kernels (Yan et al., 2023). Differing promoter variants between the high-iron (Hap1) and low-iron (Hap2) haplotypes drive variable expressions of the transcription factor in basal endosperm-transformed cells. Higher ZmNAC78 levels upregulate the downstream iron transporters ZmHMA8, ZmYSL11, and ZmNRAMP3, increasing loading into the endosperm. This finding reveals the inherent untapped genetic potential of these plants for sustainably biofortifying essential nutrients in cereal crops. Unlike some previous biofortification efforts that enhanced iron in other crops by targeting known metal homeostasis genes such as iron-regulated metal transporters, ferric chelate reductase, or nicotianamine synthase (Uauy et al., 2006; Vasconcelos et al., 2017; Kong et al., 2022; Wu et al., 2023), this research uniquely leveraged natural variation in the previously uncharacterized transcription factor ZmNAC78 to drive iron loading specifically in maize grains. Moreover, prior attempts to biofortify iron in maize faced tradeoffs between nutrient density and yield; increased kernel iron often accompanied yield penalties (Long et al., 2004). By exploiting natural ZmNAC78 variation to selectively upregulate iron transport pathways during early grain filling, iron content can be elevated without impacting overall grain yield. This approach overcame key barriers that had challenged prior maize biofortification programs. Further characterization of crop-specific molecular mechanisms regulating micronutrient distribution can help expand the arsenal of targets for tailored biofortification across diverse staple foods. The discovery of natural genetic variation in ZmNAC78 provides an opportunity to selectively breed maize varieties that exhibit both high grain yield and elevated iron concentrations (Yan et al., 2023). ZmNAC78 exhibited elevated expression levels in the corn endosperm during the 16–24-d period after pollination. This timeframe corresponds to the active accumulation of nutrients in the corn kernels. By utilizing the discovery, scientists can cultivate maize with the iron content in the kernels greatly increased to 70.5 mg/kg, which is more than twice the iron content in common maize varieties. As the authors demonstrated, molecular markers can now rapidly identify maize lines harboring promoter variants associated with superior iron loading (Yan et al., 2023). This approach will enable rapid integration of these favorable alleles into elite maize germplasm through marker-assisted breeding schemes. Enrichment of local African maize landraces with bioavailable iron could be a cost-effective and sustainable method of reaching rural farming communities impacted by deficiency (Bouis and Saltzman, 2017). The researchers also shed light on the underlying pathway facilitating iron transfer into maize kernels. Iron appears to be loaded through the basal endosperm transfer cell layer during early grain-filling stages (Yan et al., 2023). ZmNAC78 acts specifically within this tissue to switch on critical iron-transport genes, including ZmHMA8, ZmYSL11, and ZmNRAMP3 (Yan et al., 2023). These findings point to the essential role of this transport machinery in enriching iron within the maize endosperm. Differential regulation of iron loading pathways likely explains variable nutritional profiles across cereal crop species (Kong et al., 2022). This knowledge gap has previously hampered biofortification efforts in nutrient-poor crops such as maize. However, questions still remain regarding the systemic impacts of enhanced ZmNAC78 expression. Future studies should investigate the nutrient-balancing effects and stress responses that may occur as a consequence of increased iron delivery. If ZmNAC78 also inadvertently triggers senescence pathways or disrupts source-sink partitioning of other minerals, the breeding scheme could require refinement (Uauy et al., 2006). Field trials across diverse environments will clarify the optimal expression levels for preventing unintended nutritional imbalances. As biofortified lines are outcrossed with local varieties, consistent phenotyping must ensure that iron density is preserved without introducing negative traits (Vasconcelos et al., 2017). Additionally, the bio-accessibility of enhanced iron stores under actual food preparation methods merits further analysis. Using common household processing techniques, researchers can approximate the nutritional fractions digestible for human absorption (Huey et al., 2023). This would provide realistic estimates of iron status improvements achievable through the dietary inclusion of biofortified maize meal. Researchers should also explore synergies with other interventions aiming to bolster iron intake. Multi-pronged approaches coupling biofortification, supplementation, fortification, and dietary diversification may yield optimal nutritional outcomes. Iron-dense biofortified crops could amplify the protective effects of iron supplements frequently used to target high-risk groups. Combining solutions tailored to regional contexts could accelerate progress against iron deficiency (Ofori et al., 2022). Nonetheless, these discoveries represent a major step toward addressing the longstanding challenge of iron deficiency and nutritional security in sub-Saharan Africa (Sahu and Liu, 2023; Yan et al., 2023). Through further development, farmer adoption of iron-enriched maize cultivars could significantly alleviate malnutrition for millions of people in the developing world (Ofori et al., 2022; Huey et al., 2023). This research highlights the immense potential of biofortification to improve nutrition and health among those dependent on nutrient-poor staple crops. Sustained investment and multisectoral commitment are critical to realizing the public health promise of biofortified crops. This work is part of the 10KP (Ten Thousand Plant Genome Sequencing) project https://db.cngb.org/10kp/. This work is also supported by China National GeneBank (CNGB; https://www.cngb.org/). The author declares no conflict of interest. S.K.S. conceived and wrote the manuscript.