Nat Med. 2026 Jan 14. doi: 10.1038/s41591-025-04105-8. Online ahead of print.

ABSTRACT

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

PMID:41535386 | DOI:10.1038/s41591-025-04105-8

Front Immunol. 2025 Oct 14;16:1668630. doi: 10.3389/fimmu.2025.1668630. eCollection 2025.

ABSTRACT

AIMS AND OBJECTIVES: This study aimed to identify immunologically relevant transcriptomic and proteomic biomarkers in hepatocellular carcinoma (HCC) and to characterize their B-cell epitopes for potential integration into nanomaterial-based biosensors and immunomodulatory platforms for early diagnosis and targeted therapy.

METHODS: We conducted a comprehensive multi-omics analysis by integrating transcriptomic (TCGA-LIHC) and proteomic data to identify differentially expressed genes (DEGs) in HCC. Protein-protein interaction networks and pathway enrichment were used to prioritize hub genes. Five candidate biomarkers, RFC2, HSP90AB1, YWHAZ, CYP2E1, and ADH4, were selected for qRT-PCR and serum ELISA validation in clinical cohorts comprising 85 HCC patients and 50 healthy controls. B-cell epitope prediction was performed using BepiPred 2.0 and validated through synthetic peptide-based ELISA in the same cohort to assess immunoreactivity. Diagnostic performance was evaluated using ROC curve analysis.

RESULTS: RFC2, HSP90AB1, and YWHAZ were significantly upregulated (|log2FC|>0.2) and showed high serological expression, whereas CYP2E1 and ADH4 were consistently downregulated. Predicted B-cell epitopes from RFC2, HSP90AB1, and YWHAZ exhibited strong immunoreactivity (AUC>0.84), indicating their diagnostic potential. Enrichment analysis revealed that upregulated DEGs were involved in cell cycle and mitotic progression, while downregulated genes were linked to immune suppression and metabolic dysfunction. These validated immunogenic epitopes offer promising anchors for nanomaterial-functionalized biosensors, such as gold nanoparticle-conjugated ELISA, graphene-based electrochemical platforms, and peptide-coated quantum dots, for ultrasensitive and multiplexed HCC detection.

CONCLUSION: By integrating transcriptomic and proteomic screening with epitope-level validation, we identified a novel panel of immunogenic biomarkers suitable for nanomaterial-enabled diagnostics in HCC. These findings support the translational potential of peptide-nano scaffold conjugates in developing minimally invasive, immune-responsive biosensing and therapeutic tools tailored for early-stage liver cancer management.

PMID:41164201 | PMC:PMC12558944 | DOI:10.3389/fimmu.2025.1668630