Cadmium (Cd) is a widespread toxic heavy metal, and exposure to Cd is a growing environmental health concern. The molecular mechanism of Cd cytotoxicity is complicated and still not well understood, and treatment options for Cd cytotoxicity are lacking. Currently, only a limited number of Cd-targeted proteins have been identified. Here, we used Cd-immobilized metal ion affinity chromatography (Cd-IMAC) coupled with LC-MS/MS technique to detect putative Cd-binding proteins in human cells, and nucleophosmin (NPM1) was identified as the top Cd-binding protein. We found that Cd bound exclusively to the methionine/aspartate (M/D)-rich region (MEDSMDMDM) of NPM1, and NPM1 was essential for Cd-induced apoptosis. Furthermore, Cd could trigger intracellular nucleolar stress by causing nucleoplasmic translocation of NPM1 and decreasing pre-rRNA levels through binding to the M/D-rich region of NPM1. Interestingly, we discovered that a short peptide containing only the M/D-rich region of NPM1 could effectively mitigate Cd toxicity, both in vitro and in vivo. Specifically, the synthetic M/D-rich peptide demonstrated significant protection against Cd toxicity, particularly in the liver. It significantly reduced Cd concentration, suppressed the upregulation of blood ALT and AST levels, and alleviated liver inflammation in Cd-exposed BALB/c mice. This study reveals a novel mechanism of Cd cytotoxicity through NPM1-regulated nucleolar stress and apoptosis. Additionally, it identifies a short peptide with strong clinical potential to counteract Cd toxicity.

The human eukaryotic translation initiation factor 5A (EIF5A) family consists of three members, namely EIF5A1, EIF5A2, and EIF5AL1. Recent studies have shown that the expression of EIF5As is related to many human diseases, such as diabetes, viral infection, central nervous system injury, and cancer. Among them, EIF5A1 plays different functions in various cancers, possibly as a tumor-suppressor or oncogene, while EIF5A2 promotes the occurrence and development of cancer. Yet, the biological function of EIF5AL1 is not being studied so far. Interestingly, although there are only three amino acid (at residues 36, 45, and 109) differences between EIF5A1 and EIF5AL1, we demonstrate that only EIF5A1 can be hypusinated while EIF5AL1 cannot, and EIF5AL1 has a tumor-suppressor-like function by inhibiting cell proliferation and migration. We also show that EIF5AL1 protein turnover is mediated through the proteasomal pathway, and EIF5AL1 protein turnover is much faster than that of EIF5A1, which may explain their differential protein expression level in cells. By engineering single and double mutations on these three amino acids, we pinpoint which of these amino acids are critical for hypusination and protein stability. The data of this work should fill in the gaps in EIF5As research and pave the way for future studies on EIF5AL1.

Background: Previously, we found that an uncharacterized protein CXorf38 is significantly downregulated in human ZIP8-knockout (KO) cells. Given that ZIP8 regulates essential micronutrients linked to diseases including cancer, this study aims to characterize CXorf38 and evaluate its role in lung adenocarcinoma. Methods: iTRAQ-based proteomics was previously used to identify the abundance of proteins in ZIP8-KO cells. Cell proliferation and colony formation assays were used to examine the function of CXorf38 by overexpressing the gene in lung adenocarcinoma cell lines. Kaplan–Meier survival analysis was used to assess the prognostic value of CXorf38, while TCGA clinical database analysis was used to evaluate its expression in lung cancer tissues, particularly in smokers. Bioinformatics analyses (GO, KEGG, PPI, and ICI) were performed on CXorf38-coexpressed genes derived from patients with lung cancer. Results: CXorf38 overexpression suppressed lung cancer cell proliferation and colony formation, suggesting a tumor-suppressive role. Higher CXorf38 expression correlated with improved survival in patients with lung adenocarcinoma, but not in lung squamous cell carcinoma. Clinical data showed CXorf38 downregulation with lung cancer tissues of smokers, indicating a potential role in smoking-induced cancer progression and treatment. Functional analysis using bioinformatics linked CXorf38 to immune response regulation, suggesting involvement in the tumor immune microenvironment. Conclusions: Our study reveals for the first time that CXorf38 is a potential tumor suppressor, prognostic biomarker, and/or tumor immune regulator in lung adenocarcinoma—further research is warranted to explore its role in tumor immunity and its therapeutic potential.