Being a staple food, wheat (Triticum aestivum) nutritionally fulfills all requirements of human health and also serves as a significant link in the food chain for the ingestion of pollutants by humans and animals. Therefore, the presence of the heavy metals such as lead (Pb) and cadmium (Cd) in soil is not only responsible for the reduction of wheat crop yield but also the potential threat for human and animal health. However, the link between DNA methylation and heavy metal stress tolerance in wheat has not been investigated yet. In this study, eight high yielding wheat varieties were screened based on their phenotype in response to Pb stress. Out of these, Pirsabak 2004 and Fakhar-e-sarhad were identified as Pb resistant and sensitive varieties, respectively. In addition, Pirsabak 2004 and Fakhar-e-sarhad varieties were also found resistant and sensitive to Cd and Zinc (Zn) stress, respectively. Antioxidant activity was decreased in Fakhar-e-sarhad compared with control in response to Pb/Cd/Zn stresses, but Fakhar-e-sarhad and Pirsabak 2004 accumulated similar levels of Pb, Cd and Zn in their roots. The expression of Heavy Metal ATPase 2 (TaHMA2) and ATP-Binding Cassette (TaABCC2/3/4) metal detoxification transporters are significantly upregulated in Pirsabak 2004 compared with Fakhar-e-sarhad and non-treated controls in response to Pb, Cd and Zn metal stresses. Consistent with upregulation of metal detoxification transporters, CG DNA hypomethylation was also found at the promoter region of these transporters in Pirsabak 2004 compared with Fakhar-e-sarhad and non-treated control, which indicates that DNA methylation regulates the expression of metal detoxification transporters to confer resistance against metal toxicity in wheat. This study recommends the farmers to cultivate Pirsabak 2004 variety in metal contaminated soils and also highlights that DNA methylation is associated with metal stress tolerance in wheat.

The persistent nature of lead (Pb) and cadmium (Cd) in the environment severely affects plant growth and yield. Conversely, plants acquire zinc (Zn) from the soil for their vital physiological and biochemical functions. However, the interplay and coordination between essential and toxic metals for their uptake and translocation and the putative underlying epigenetic mechanisms have not yet been investigated in maize. Here, we report that the presence of Zn facilitates the accumulation and transport of Pb and Cd in the aerial parts of the maize plants. Moreover, the Zn, Pb, and Cd interplay specifically interferes with the uptake and translocation of other divalent metals, such as calcium and magnesium. Zn, Pb, and Cd, individually and in combinations, differentially regulate the expression of DNA methyltransferases, thus alter the DNA methylation levels at the promoter of Zinc-regulated transporters, Iron-regulated transporter-like Protein (ZIP) genes to regulate their expression. Furthermore, the expression of histone deacetylases (HDACs) varies greatly in response to individual and combined metals, and HDACs expression showed a negative correlation with ZIP transporters. Our study highlights the implication of DNA methylation and histone acetylation in regulating the metal stress tolerance dynamics through Zn transporters and warns against the excessive use of Zn fertilizers in metal contaminated soils.

Background: Glioblastoma is the most aggressive primary brain tumor, with a poor prognosis and limited treatment options. Natural killer (NK) cell therapy is a promising immunotherapeutic strategy; yet, its efficacy remains limited. We evaluated FT538, a clinical-grade NK product derived from induced pluripotent stem cells (iPSCs), in glioblastoma models. Methods: FT538, engineered with a high-affinity noncleavable CD16 Fc receptor, a membrane-bound IL-15/IL-15Rα fusion protein, and CD38 knockout, was tested against 13 patient-derived glioblastoma stem-like cells (GSCs) in vitro and in orthotopic xenograft models. Intracranial persistence and neurotoxicity were assessed in mice. Surface proteomics identified therapeutic targets, and a B7-H3–targeted tri-specific killer engager (TriKE) was evaluated with FT538 and NKG2C+ adaptive NK cells. Results: Glioblastoma stem-like cells were classified as sensitive (38%), moderately sensitive (38%), or resistant (23%) to FT538. Intracranial administration in mice was well tolerated, persisted for at least 35 days, and caused no neurotoxicity. A single intratumoral dose induced complete regression in sensitive xenografts. Surface profiling identified B7-H3 as a target to overcome resistance. Combination therapy with FT538 and a B7-H3 TriKE enhanced antitumor efficacy in resistant models, an effect also observed with adaptive NK cells. Conclusions: FT538 exhibits potent tumoricidal activity in 77% of GSC lines (NK-sensitive and moderately sensitive), with curative potential in sensitive models, and demonstrates favorable persistence and tolerability in vivo. B7-H3–targeted TriKE restores NK sensitivity in resistant tumors. These findings provide a strong preclinical rationale for further clinical evaluation of FT538, alone or combined with B7-H3–targeted TriKE, for glioblastoma and other solid tumors.