Background 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a heterocyclic aromatic amine, is a potent carcinogen to which people are exposed through high-temperature-cooked foods and which increases the risk of pancreatic ductal adenocarcinoma (PDAC). However, the oncogenic mechanisms of MeIQx and its metabolites in pancreatic tissue are not yet fully understood. This study aims to elucidate the molecular pathways and immune evasion mechanisms involved in PDAC development following MeIQx exposure from a systems biology perspective. Methods A comprehensive network toxicology workflow was applied to MeIQx and its four major metabolites (N-OH-MeIQx, N-O-Ac-MeIQx, MeIQx-C8dG, and MeIQx-N2-Sulfamate). Toxicity profiling was performed using ProTox-3.0; target prediction was conducted using SwissTargetPrediction, PharmMapper, and SEA; and disease gene mapping was performed using GeneCards, OMIM, and DISEASES. A protein–protein interaction (PPI) network was constructed using STRING v11.5, and central genes were identified. Differential expression and survival analyses were performed using the GEPIA2 platform on TCGA-PAAD and GTEx data (tumor n = 179, normal n = 171). The immune microenvironment was analyzed using ssGSEA, while molecular interactions were evaluated using CB-Dock2 and AutoDock Vina. Results ProTox-3.0 analyses predicted high mutagenicity (0.97) for MeIQx and high neurotoxicity (0.90) and mutagenicity (0.94) for N-O-Ac-MeIQx. Network analysis identified AKT1 and CTNNB1 as key hub genes interacting with MeIQx. GEPIA2 analysis showed that AKT1 was significantly upregulated in PDAC tumors compared to normal tissue (p<0.05). Although survival analysis indicated that AKT1 mRNA levels were not an independent prognostic factor, immune profile analyses revealed that AKT1 exhibited a negative correlation with CD8 + T cells (r = −0.297) and a positive correlation with M2 macrophages (r = + 0.207). Furthermore, it was found that the immune checkpoints B7-H3 and SIGLEC15 were selectively upregulated in tumors with high AKT1 levels. In molecular binding assays, the MeIQx-C8dG adduct exhibited the highest binding affinity (−9.9 kcal/mol) for AKT1. Conclusion This study presents the first comprehensive network toxicology characterization of MeIQx in PDAC. The findings suggest that MeIQx exposure may promote carcinogenesis by activating the AKT1 signaling pathway and triggering an immune evasion mechanism via the B7-H3/SIGLEC15 axis, which is independent of PD-L1. These data provide new biomarker candidates regarding the role of diet-derived carcinogens in pancreatic cancer progression.

Integrative network toxicology of meIQx and its metabolites in pancreatic cancer

期刊论文
发表日期：

2026年7月28日

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Hasan ÖZ

摘要

Background

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a heterocyclic aromatic amine, is a potent carcinogen to which people are exposed through high-temperature-cooked foods and which increases the risk of pancreatic ductal adenocarcinoma (PDAC). However, the oncogenic mechanisms of MeIQx and its metabolites in pancreatic tissue are not yet fully understood. This study aims to elucidate the molecular pathways and immune evasion mechanisms involved in PDAC development following MeIQx exposure from a systems biology perspective.

Methods

A comprehensive network toxicology workflow was applied to MeIQx and its four major metabolites (N-OH-MeIQx, N-O-Ac-MeIQx, MeIQx-C8dG, and MeIQx-N2-Sulfamate). Toxicity profiling was performed using ProTox-3.0; target prediction was conducted using SwissTargetPrediction, PharmMapper, and SEA; and disease gene mapping was performed using GeneCards, OMIM, and DISEASES. A protein–protein interaction (PPI) network was constructed using STRING v11.5, and central genes were identified. Differential expression and survival analyses were performed using the GEPIA2 platform on TCGA-PAAD and GTEx data (tumor n = 179, normal n = 171). The immune microenvironment was analyzed using ssGSEA, while molecular interactions were evaluated using CB-Dock2 and AutoDock Vina.

Results

ProTox-3.0 analyses predicted high mutagenicity (0.97) for MeIQx and high neurotoxicity (0.90) and mutagenicity (0.94) for N-O-Ac-MeIQx. Network analysis identified AKT1 and CTNNB1 as key hub genes interacting with MeIQx. GEPIA2 analysis showed that AKT1 was significantly upregulated in PDAC tumors compared to normal tissue (p<0.05). Although survival analysis indicated that AKT1 mRNA levels were not an independent prognostic factor, immune profile analyses revealed that AKT1 exhibited a negative correlation with CD8 + T cells (r = −0.297) and a positive correlation with M2 macrophages (r = + 0.207). Furthermore, it was found that the immune checkpoints B7-H3 and SIGLEC15 were selectively upregulated in tumors with high AKT1 levels. In molecular binding assays, the MeIQx-C8dG adduct exhibited the highest binding affinity (−9.9 kcal/mol) for AKT1.

Conclusion

This study presents the first comprehensive network toxicology characterization of MeIQx in PDAC. The findings suggest that MeIQx exposure may promote carcinogenesis by activating the AKT1 signaling pathway and triggering an immune evasion mechanism via the B7-H3/SIGLEC15 axis, which is independent of PD-L1. These data provide new biomarker candidates regarding the role of diet-derived carcinogens in pancreatic cancer progression.