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25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 28 February 2027 | Viewed by 5176

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Dr. Marco E. M. Peluso

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Cancer Risk Factor Branch, Regional Cancer Prevention Laboratory, Study, Prevention and Oncology Network Institute (ISPRO), 50139 Florence, Italy
Interests: genetic damage; oxidative stress; DNA adducts; epigenetics; mutations; carcinogenesis; molecular epidemiology
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Special Issue Information

Dear Colleagues,

By identifying biomarkers of exposure and effect, molecular toxicology can elucidate the mechanisms of toxicity of environmental agents and inform risk assessment and policy decisions, focusing on the risks posed to human health. Improved understanding can allow for more precise diagnosis, personalized treatment strategies, and a better knowledge of how environmental agents contribute to the development of human diseases. Therefore, this Special Issue, 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology, aims to collect original research contributions on the most recent investigations in this field that can help to delucidate the interactions between chemical molecules and organisms by providing tools to understand chronic diseases, including cancer, at its fundamental molecular level. Topics of interest include, but are not limited to, the study of defined xenobiotics compounds such as cancerogenic agents, metals, endocrine and epigenetic disruptors, and the association between exposure to toxic substances and the diagnosis of human diseases by using in vivo and in vitro models, as well as case–control and cross-sectional approaches. We hope that this Special Issue will prompt advances in molecular toxicology as well its application in cancer diagnostics.

Dr. Marco E. M. Peluso
Guest Editor

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Keywords

molecular toxicology
biomarkers
mechanisms of toxicity
xenobiotics
cancer diagnosis

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Published Papers (5 papers)

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Research

23 pages, 52446 KB

Open AccessArticle

Gaseous Air Pollutant Exposure and Atherosclerosis: A Systematic Study Integrating Multi-Omics and Network Toxicology

by Husileng Hai, Qianhe Wang, Juan Li, Jie Wang, Xijuan Jiang and Maojuan Guo

Int. J. Mol. Sci. 2026, 27(16), 7381; https://doi.org/10.3390/ijms27167381 - 18 Aug 2026

Abstract

Gaseous air pollution is a major environmental risk factor for atherosclerosis, yet the specific molecular networks linking Gaseous air pollution to atherosclerosis are not fully characterized. This study aimed to elucidate how gaseous pollutants drive atherosclerosis using a multi-level framework integrating network toxicology, nine machine-learning algorithms, bulk and single-cell/spatial transcriptomics, molecular docking, clinical tissue/serum validation, and in vitro pollutant-exposure assays. A conserved RXRA–MMP9–TNF axis was identified as a core molecular network linking pollutant exposure to atherosclerosis. Single-cell and spatial transcriptomics showed broad expression of RXRA (Retinoid X Receptor Alpha) in vascular stromal and endothelial cells and its association with xenobiotic and lipid metabolism, whereas MMP9 (Matrix Metallopeptidase 9) and TNF (Tumor Necrosis Factor) were enriched in macrophages, T cells, and mast cells within plaques, correlating with immune cell infiltration. Multiple pollutants displayed high binding affinity to these proteins. Clinical samples showed upregulation of these targets in atherosclerotic tissue and serum. Toluene exposure in THP-1-derived macrophages significantly increased RXRA, MMP9, and TNF mRNA and protein levels. These findings highlight an immune–metabolic interplay centered on the RXRA–MMP9–TNF axis in Gaseous air pollution-driven atherosclerosis, supporting these molecules as candidate biomarkers for environmental health strategies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology)

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14 pages, 4262 KB

Open AccessArticle

Wild-Type p53 Protein Enhances APR-246-Induced Cytotoxicity in Acute Myeloid Leukemia and Normal Hematopoietic Stem/Progenitor Cells

by John B. Cart, David Zhu, Lucas Norris, Sadhna O. Piryani, Li-Chan Chang, Christine E. Eyler and Chang-Lung Lee

Int. J. Mol. Sci. 2026, 27(11), 4974; https://doi.org/10.3390/ijms27114974 - 30 May 2026

Viewed by 754

Abstract

APR-246 (Eprenetapopt) is a small-molecule drug that restores the activity of dysfunctional p53 proteins caused by missense mutations that affect the DNA-binding domain. However, recent studies suggest that APR-246 can also induce cell death in cancer cells that carry wild-type (WT) TP53. Here, we aimed to determine the impact of APR-246 on the survival of acute myeloid leukemia (AML) cells using isogenic Molm13 cells that harbor WT TP53, a missense mutation of TP53^R175H, or a biallelic deletion of TP53 (TP53^−/−). Our results showed that Molm13 TP53^−/− cells were significantly more resistant to APR-246-induced cell death compared with their Molm13 TP53^R175H/− mutant and Molm13 TP53^+/+ counterparts. In addition, knockdown of TP53 significantly reduced cytotoxicity induced by APR-246 in two TP53 WT AML cell lines (MV4-11 and OCI-AML2). Moreover, APR-246 markedly decreased the clonogenicity of TP53 WT hematopoietic stem/progenitor cells (HSPCs) isolated from humans and mice. In contrast, biallelic loss of TP53, but not TP53 missense mutation, significantly increased the resistance of mouse HSPCs to APR-246. Mechanistically, the loss of functional p53 proteins in Molm13 and MV4-11 cells decreased intrinsic apoptosis and impaired the production of cellular reactive oxygen species (ROS) induced by APR-246. Together, our results indicate that, in at least a subset of AML cell lines and normal HSPCs, APR-246-induced ROS production and cytotoxicity are enhanced in the presence of WT p53 proteins. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology)

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21 pages, 1873 KB

Open AccessArticle

Effects of Maternal Tetramethyl Bisphenol F Exposure on Neurodevelopment and Behavior in Mouse Offspring

by Inho Hwang, Sun Kim and Eui-Bae Jeung

Int. J. Mol. Sci. 2026, 27(7), 3299; https://doi.org/10.3390/ijms27073299 - 5 Apr 2026

Viewed by 991

Abstract

Bisphenol A (BPA) has long been used in plastics, resins, and food packaging materials; however, extensive research has demonstrated its reproductive, developmental, and endocrine-disrupting effects. Consequently, BPA has been increasingly restricted and replaced with structural analogues. Among these, tetramethyl bisphenol F (TMBPF) has emerged as one of the most widely used substitutes, particularly in epoxy resins and food-can coatings. Although initially regarded as a safer alternative, accumulating evidence suggests that TMBPF may exert multiple toxicological effects, raising concerns about its potential developmental neurotoxicity. The present study aimed to investigate the neurodevelopmental effects of TMBPF using both in vitro and in vivo approaches. First, a developmental neurotoxicity assay employing Sox1−GFP mouse embryonic stem cells was used to evaluate cytotoxicity using the cell counting kit-8 assay and neural differentiation based on green fluorescent protein (GFP) fluorescence intensity. The results indicated developmental neurotoxic potential according to the established discrimination index. Subsequently, pregnant and lactating mice were exposed to TMBPF daily from gestational day 10.5 to postnatal day 20, and their offspring were assessed for behavioral performance as well as changes in the expression of neurodevelopment-related genes in the brain. Behavioral analyses encompassed multiple domains, including memory and learning, social behavior, anxiety-related responses, and spontaneous locomotor activity, suggesting alterations in these functional outcomes. Molecular analyses further demonstrated changes associated with dopaminergic and cholinergic signaling, synaptic plasticity, neuronal activity markers, neuropeptides, and inflammatory pathways. Collectively, these findings provide the first evidence in a mammalian model that maternal exposure to TMBPF may influence offspring neurodevelopment. These findings suggest potential implications for human exposure to TMBPF, particularly through food-contact materials, and warrant further mechanistic and dose–response studies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology)

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28 pages, 10855 KB

Open AccessArticle

Molecular Mechanisms of Aspartame-Induced Kidney Renal Papillary Cell Carcinoma Revealed by Network Toxicology and Molecular Docking Techniques

by Chenjie Huang, Lulu Wei, Wenqi Yuan, Yaohong Lu, Gedi Zhang and Ziyou Yan

Int. J. Mol. Sci. 2026, 27(1), 77; https://doi.org/10.3390/ijms27010077 - 21 Dec 2025

Cited by 3 | Viewed by 1414

Abstract

Aspartame, a widely used artificial sweetener, has been linked to various cancers, including kidney renal papillary cell carcinoma (KIRP). However, the molecular mechanisms underlying this association remain unclear. This study employed network toxicology and molecular docking to investigate potential mechanisms of aspartame-induced KIRP. Differentially expressed genes from TCGA were intersected with aspartame targets and KIRP-related genes, yielding 61 common targets. GO and KEGG analyses revealed enrichment in extracellular matrix degradation, signaling pathways, and immune microenvironment regulation. Univariate Cox regression identified 23 prognostically significant genes, from which multifactorial Cox regression with stepwise selection determined 8 core genes (APLNR, CYP2C19, EDNRA, KLK5, F2R, RAD51, AURKA, and TLR2). A risk model was constructed and validated through VIF analysis, Schoenfeld residual testing, and internal validation using a training–validation split. SHAP analysis identified EDNRA as the primary driver gene. Survival analysis demonstrated that the model effectively stratified KIRP patients, with risk score and tumor stage serving as independent prognostic factors. Molecular docking confirmed stable binding between aspartame and core target proteins. These findings provide mechanistic insights into aspartame-induced KIRP pathogenesis and establish a foundation for future experimental validation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology)

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18 pages, 5040 KB

Open AccessArticle

B-Cell Receptor-Associated Protein 31 Deficiency Aggravates Ethanol-Induced Liver Steatosis and Liver Injury via Attenuating Fatty Acid Oxidation and Glycogen Synthesis

by Shubin Yu, Yaodong Xia, Chunyan Zhang, Xiangyue Han, Xiaoyue Feng, Liya Li, Hang Ma and Jialin Xu

Int. J. Mol. Sci. 2025, 26(24), 12173; https://doi.org/10.3390/ijms262412173 - 18 Dec 2025

Cited by 1 | Viewed by 1221

Abstract

Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31′s biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspartate transaminase (31.4%, p < 0.05) levels compared to WT mice. Increased malondialdehyde (8.5%, p < 0.05) and reduced superoxide dismutase (22.8%, p < 0.05) in BAP31-LKO mice indicate exacerbated liver injury. Furthermore, BAP31 deficiency increased triglyceride (35.7%, p < 0.05) and free fatty acid (16.2%, p < 0.05) accumulation following ethanol treatment, while the expression of fatty acid oxidation-related genes, including Pparα, Cd36, Fatp2, Cpt2, and Acox1, was reduced in BAP31-LKO mice. The mRNA levels of Xbp1, Xbp1s, and Chop, as well as protein levels of p-eIF2α, IRE1α, GRP78, and CHOP, were increased in BAP31-LKO mice compared to WT controls, indicating aggravated ethanol-induced ER stress. Hepatic glycogen content was also reduced in BAP31-LKO mice, along with reduced Ppp1r3c expression, demonstrating impaired glycogen synthesis. Consistently, BAP31 knockdown amplified ethanol-induced lipid accumulation, inflammation, impaired glycogen storage, ER stress, and suppression of Pparα signaling in HepG2 cells. Together, these findings demonstrate that BAP31 deficiency exacerbates ethanol-induced liver steatosis, inflammation, and liver injury by impairing fatty acid oxidation and glycogen synthesis, and by amplifying ER stress responses. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology)

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