International Journal of Molecular Sciences

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Open AccessArticle

Overexpression of FGFR2 in Mandibular Ameloblastoma Is Potentially Associated with Gene Amplification and Deletion

by Nattanit Boonsong, Nakarin Kitkumthorn, Puangwan Lapthanasupkul, Kittipong Laosuwan, Wacharaporn Thosaporn, Jutamad Makyoo and Anak Iamaroon

Int. J. Mol. Sci. 2026, 27(8), 3443; https://doi.org/10.3390/ijms27083443 - 12 Apr 2026

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Abstract

Ameloblastoma (AM) is a common locally invasive benign odontogenic tumor in Asian populations. Although fibroblast growth factor receptor 2 (FGFR2) mutations have been reported in AM, FGFR2 amplification, the predominant form of FGFR2 aberration in human cancers, remains unexplored. This study [...] Read more.

Ameloblastoma (AM) is a common locally invasive benign odontogenic tumor in Asian populations. Although fibroblast growth factor receptor 2 (FGFR2) mutations have been reported in AM, FGFR2 amplification, the predominant form of FGFR2 aberration in human cancers, remains unexplored. This study aimed to evaluate FGFR2 protein expression, FGFR2 gene copy number variations, and their associations with demographic and clinico-radio-pathological parameters in mandibular AM. Eighty-seven cases of mandibular AM and 10 dental follicle (DF) specimens were included. FGFR2 protein expression was assessed by immunohistochemistry, and gene copy number variations were analyzed using the quantitative real-time polymerase chain reaction (qPCR) technique. Clinical data, including age, gender, tumor size, radiographic features, histological subtype, and recurrence history, were examined for associations with FGFR2 alterations. FGFR2 protein overexpression was observed in 95.4% of AM cases and was not significantly associated with demographic or clinico-radio-pathological variables. FGFR2 gene amplification was detected in 52.5% of cases, while 8.2% showed gene deletion. Notably, 50.8% of cases exhibited concurrent FGFR2 amplification and overexpression, and all cases with FGFR2 gene deletion also demonstrated FGFR2 overexpression. These findings suggest that FGFR2 gene amplification and deletion may contribute to FGFR2 overexpression and play a significant role in the molecular pathogenesis of mandibular AM. Full article

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

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19 pages, 1973 KB

Open AccessArticle

A Whole-Exome Sequencing-Based Exploration of Chronic Kidney Disease of Unknown Etiology (CKDu) in an Endemic Population in Sri Lanka

by Wesley Tom, Chiran Weerakoon, Nirmalee Fernando, Isuru Hasantha, Manoj Bandara, Gary Krzyzanowski, Shanika Nanayakkara, Dominic Cosgrove, Nishantha Nanayakkara and M. Rohan Fernando

Int. J. Mol. Sci. 2026, 27(8), 3369; https://doi.org/10.3390/ijms27083369 - 9 Apr 2026

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Abstract

A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30–60 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension [...] Read more.

A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30–60 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension and is characterized by tubulointerstitial damage, including tubular atrophy, interstitial inflammation, and fibrosis. Epidemiological studies showed familial clustering, suggesting an underlying genetic predisposition. This study aimed to identify genetic variants associated with CKDu in Sri Lankan populations using whole-exome sequencing (WES). Eighty-six individuals (47 CKDu patients and 39 controls) were recruited from endemic and non-endemic regions. Physiological, biochemical, and geographic parameters were recorded. DNA extracted from blood was subjected to WES to identify variants associated with CKDu. Results: A total of 171 unique variants across 121 genes were identified. Among the most prevalent genes were ATXN3, LFNG, PNLDC1, LINC02456, and HLA-DRB1. In the case–control comparison, only LFNG showed statistically significant enrichment in affected individuals, whereas signals in ATXN3, PNLDC1, and LINC02456 were not statistically significant, but have an association with renal dysfunction, and thus are included as hypothesis-generating variant observations. HLA-DRB1 variants showed trends toward a protective haplotype. LFNG showed the greatest prevalence in affected individuals (71.7%), followed by PNLDC1 (63%), ATXN3 (56%), FIP1L1 (41%), and HLA-DRB1 (32%). Conclusion: Findings suggest genetic variants in combination with environmental factors may contribute to CKDu susceptibility in the Sri Lankan population. We underscore the multi-factorial nature of CKDu and highlight the need for integrative genomic and environmental research to elucidate disease mechanisms and inform targeted prevention strategies. Full article

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

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23 pages, 6220 KB

Open AccessArticle

Genetic Regulation of Monocyte MicroRNAs and Their Implication in Musculoskeletal Diseases: A Cross-Ancestry Expression Quantitative Trait Loci and Imputation Study

by Yong Liu, Kuan-Jui Su, Yun Gong, Bo Tian, Anqi Liu, Zhe Luo, Qing Tian, Chuan Qiu, Hui Shen, Hong-Mei Xiao and Hong-Wen Deng

Int. J. Mol. Sci. 2026, 27(6), 2818; https://doi.org/10.3390/ijms27062818 - 20 Mar 2026

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Abstract

This study investigated the genetic regulation of microRNA (miRNA) expression in monocytes and its potential role in musculoskeletal diseases. We mapped expression quantitative trait loci (eQTLs) for miRNAs using data from 281 Caucasian (CAU) and 170 African American (AA) individuals, constructed ancestry-specific models [...] Read more.

This study investigated the genetic regulation of microRNA (miRNA) expression in monocytes and its potential role in musculoskeletal diseases. We mapped expression quantitative trait loci (eQTLs) for miRNAs using data from 281 Caucasian (CAU) and 170 African American (AA) individuals, constructed ancestry-specific models to impute miRNA expression from genotype data, and applied these models to test associations with osteoporosis and sarcopenia. Analysis identified 468 and 2653 independent eQTLs for 61 miRNAs in CAU and 25 in AA, respectively, the majority of which were ancestry-specific. Association analyses identified 22 and 26 miRNAs associated with osteoporosis and sarcopenia, respectively, in the CAU population; corresponding findings in the African American population were 26 and 14 miRNAs. Analysis of their target genes revealed 1238 and 741 genes that were nominally associated with osteoporosis and sarcopenia in CAU; with 524 genes associated with osteoporosis and 891 associated with sarcopenia in AA. Functional enrichment analysis indicated that the target genes of the identified miRNAs are involved in disease-relevant biological processes—cell migration and motility in osteoporosis, and immune/cytokine responses in sarcopenia. This work provides insights into the genetic architecture of miRNA expression and implicates monocyte miRNAs in musculoskeletal diseases, underscoring the importance of including diverse ancestral backgrounds in genomic studies. Full article

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

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14 pages, 1847 KB

Open AccessArticle

Stability of c-Myc Protein in Early S Phase Is Regulated by the Interaction with PCNA

by Miriana Cardano, Ornella Cazzalini, Giusy Maraventano, Lucia A. Stivala, Laura Zannini and Ennio Prosperi

Int. J. Mol. Sci. 2026, 27(6), 2745; https://doi.org/10.3390/ijms27062745 - 18 Mar 2026

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Abstract

The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization [...] Read more.

The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization remains unclear. Here, we investigated whether c-Myc interacts with PCNA and analyzed the possible function of this association. We found a conserved interaction motif, the PCNA-interacting protein (PIP) box, in the N-terminal region of c-Myc. Confocal microscopy analysis showed co-localization with PCNA in early S-phase, but not in late S-phase cells. Co-immunoprecipitation from cell extracts and pull-down of recombinant proteins indicated a direct physical association between c-Myc and PCNA, which was confirmed in situ by the Proximity Ligation Assay (PLA). Further experiments demonstrated that c-Myc interacts with CUL4A and DDB1, components of the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex, in which PCNA functions as a cofactor. Mutations in the PIP box of c-Myc, as well as depletion of CUL4A by RNA interference, resulted in an increased stability of c-Myc protein. These results suggest that the interaction with PCNA functionally contributes to the regulation of c-Myc stability in early S phase via the CRL4 complex. Full article

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

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21 pages, 57805 KB

Open AccessArticle

A Near-Telomere-to-Telomere Genome Assembly of the Spotted Seal (Phoca largha) Reveals Genomic Architecture Underlying Skin and Fur Adaptation

by Min Zhou, Tingting Li, Xiaotong Zhu, Shenghao Liu, Bailin Cong and Linlin Zhao

Int. J. Mol. Sci. 2026, 27(6), 2618; https://doi.org/10.3390/ijms27062618 - 13 Mar 2026

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Abstract

The spotted seal (Phoca largha) is an ice-associated pinniped in the Northwest Pacific and is a subject of conservation concern under increasing environmental and anthropogenic pressures; however, genomic studies have been constrained by the absence of a high-quality reference genome. Here, [...] Read more.

The spotted seal (Phoca largha) is an ice-associated pinniped in the Northwest Pacific and is a subject of conservation concern under increasing environmental and anthropogenic pressures; however, genomic studies have been constrained by the absence of a high-quality reference genome. Here, we present a near-telomere-to-telomere (near-T2T), gap-free genome assembly of P. largha spanning 2.39 Gb and comprising 16 chromosome-length sequences, with a scaffold N50 of 184.39 Mb and high completeness (99.34% complete BUSCOs). Compared with the previous chromosome-level assembly, the new genome improves contiguity and gene-space completeness. Comparative analyses across 20 carnivoran species resolve P. largha as sister to Phoca vitulina with an estimated divergence time of ~2.1 Ma. Branch-site positive-selection analyses and gene-family evolution analyses identify lineage-associated changes, and enrichment results motivate focused investigation of integument-related gene families. Targeted analyses of keratin (KRT) and matrix metalloproteinase (MMP) families reveal contrasting chromosomal organisation and evolutionary dynamics: KRTs form large chromosomal clusters with broadly conserved synteny across Carnivora but lineage-dependent remodelling within clusters, whereas MMPs are dispersed and display largely conserved orthologous correspondence. This high-quality genome provides a high-quality resource for pinniped comparative genomics and for elucidating the genomic architecture of skin and fur adaptation. Full article

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

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14 pages, 1239 KB

Open AccessArticle

Emerging Multi-Source Transmission of SFTS Virus on a Remote Japanese Island: A One-Health Perspective

by Ryosaku Oshiro, Motoki Ihara, Catarina Harumi Oda Ibrahim, Kosuke Matsui, Xayavong Dalouny, Nhung Hong Pham Vu, Tomomi Kurashige, Qiang Xu, Shangfan Hu, Mya Myat Ngwe Tun, Yumika Takaki, Hikaru Ogushi, Daichi Setoguchi, Shinichi Katsuoka, Tatsuki Murakami, Chikara Matsumoto, Mitsuru Hattori, Naoko Hattori, Sho Miyamoto, Yusuke Sakai, Tadaki Suzuki, Hirotomo Yamanashi, Hiroyuki Murota, Takahiro Maeda, Kouichi Morita, Akira Yoshikawa and Yuki Takamatsu Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(4), 1702; https://doi.org/10.3390/ijms27041702 - 10 Feb 2026

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Abstract

Tick-borne viral infections, including severe fever with thrombocytopenia syndrome virus (SFTSV), are increasingly recognized as a significant threat to global public health owing to their rapid dissemination and high mortality rates. While isolated outbreaks within single species have been documented, reports of multi-host [...] Read more.

Tick-borne viral infections, including severe fever with thrombocytopenia syndrome virus (SFTSV), are increasingly recognized as a significant threat to global public health owing to their rapid dissemination and high mortality rates. While isolated outbreaks within single species have been documented, reports of multi-host cluster cases remain scarce. This study describes a consecutive, cross-species outbreak of severe fever with thrombocytopenia syndrome disease between April and May 2024 on a remote island in Nagasaki Prefecture that involved four cats and four humans. An interdisciplinary investigation integrating molecular phylogenetic analysis of viral genomes—including previously identified Nagasaki strains of SFTSV—and haplotype network analysis provided insights into the infection dynamics. Despite the absence of confirmed direct contact between cats and humans, four animals and one patient succumbed to the infection. Genomic analyses demonstrated high similarity to circulating Nagasaki strains, whereas haplotype analysis indicated multiple viral introduction events and complex transmission pathways, reflecting diverse sources. These findings underscore the critical need for a One Health approach—integrating human, animal, and vector surveillance—to effectively monitor, understand, and control tick-borne viruses globally, in both endemic and emerging regions. Full article

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

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24 pages, 3439 KB

Open AccessArticle

Mitogenome of Medicago lupulina L. Cultivar-Population VIK32, Line MlS-1: Dynamic Structural Organization and Foreign Sequences

by Maria E. Vladimirova, Marina L. Roumiantseva, Alla S. Saksaganskaia, Alexandra P. Kozlova, Victoria S. Muntyan, Sergey P. Gaponov, Andrey P. Yurkov, Vladimir A. Zhukov and Mikhail P. Grudinin

Int. J. Mol. Sci. 2025, 26(24), 11830; https://doi.org/10.3390/ijms262411830 - 7 Dec 2025

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Abstract

This study presents the complete assembly and analysis of the mitochondrial genome (mitogenome) of Medicago lupulina L. var. vulgaris Koch, cultivar-population VIK32, line MlS-1, which forms an effective symbiosis not only with arbuscular mycorrhiza but also with the root nodule bacteria Sinorhizobium meliloti [...] Read more.

This study presents the complete assembly and analysis of the mitochondrial genome (mitogenome) of Medicago lupulina L. var. vulgaris Koch, cultivar-population VIK32, line MlS-1, which forms an effective symbiosis not only with arbuscular mycorrhiza but also with the root nodule bacteria Sinorhizobium meliloti. The assembly, generated using a hybrid sequencing approach, revealed sequences of putative horizontal origin. These include a highly conserved open reading frame (ORF), orf279, encoding a protein structurally homologous to maturase K, yet bearing remote similarity to bacterial reverse transcriptases and CRISPR-associated proteins. We also identified sequences homologous to mitovirus RNA-dependent RNA polymerases and a fragment of the chloroplast 23S ribosomal RNA (rRNA), suggesting historical gene transfers from viruses and plastids. This work establishes a foundation for investigating the role of mitochondrial genome variation in key plant’s phenotypic traits, such as the enhanced responsiveness to arbuscular mycorrhiza observed in this agronomically valuable line. Full article

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

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10 pages, 256 KB

Open AccessCommunication

Association of DPP4 Gene Variants with Classic and DPP4 Inhibitor-Associated Bullous Pemphigoid

by Charoula Achilla, Christina Foutsitzidou, Parthena Meltzanidou, Aikaterini Patsatsi, Elizabeth Lazaridou, Glykeria Tzatzagou, Alexandros Lambropoulos and Anthoula Chatzikyriakidou

Int. J. Mol. Sci. 2025, 26(23), 11698; https://doi.org/10.3390/ijms262311698 - 3 Dec 2025

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Abstract

Bullous pemphigoid (BP), the most prevalent autoimmune blistering skin disorder, has been associated with dipeptidyl peptidase-4 inhibitor (DPP4i) treatment in type 2 diabetic patients. This study aimed to investigate the association of DPP4 gene variants, rs3788979 and rs12617656, with classic BP (cBP)- and [...] Read more.

Bullous pemphigoid (BP), the most prevalent autoimmune blistering skin disorder, has been associated with dipeptidyl peptidase-4 inhibitor (DPP4i) treatment in type 2 diabetic patients. This study aimed to investigate the association of DPP4 gene variants, rs3788979 and rs12617656, with classic BP (cBP)- and DPP4i-associated BP predisposition. Fifty-six (56) unrelated patients with cBP, 32 DPP4i-associated BP patients, 60 healthy controls, and 49 diabetic patients receiving DPP4i were included. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Statistical analyses were conducted using SPSS software. For rs3788979, the CT+TT genotypes were significantly associated with increased risk of DPP4i-associated BP compared with cBP [(Odds Ratio (OR) = 2.80, 95% Confidence Interval (CI) = 1.07–7.35; p-value = 0.034] and healthy controls (OR = 0.30, 95% CI = 0.13–0.86; p-value = 0.020). The T allele was also enriched in DPP4i-associated BP (OR = 2.57, 95% CI = 1.09–6.07; p-value = 0.027). Additionally, the TC genotype of rs12617656 (OR = 2.29, 95% CI = 1.04–5.03, p-value = 0.039) showed significant association with cBP susceptibility. These findings highlight DPP4 variants as potential BP risk factors, supporting personalized risk assessment prior to initiating gliptin therapy. Large-scale studies are warranted to validate these associations. Full article

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

19 pages, 3843 KB

Open AccessArticle

Mitochondrial Gene Regulation and Pain Susceptibility: A Multi-Omics Causal Inference Study

by Chien-Cheng Liu

Int. J. Mol. Sci. 2025, 26(17), 8690; https://doi.org/10.3390/ijms26178690 - 6 Sep 2025

Cited by 1 | Viewed by 1985

Abstract

The causal contributions of specific mitochondrial genes to common pain phenotypes remain unclear. We employed a multi-omics Mendelian randomization (SMR) approach, integrating QTL data (expression, methylation, protein) for mitochondrial genes with GWAS summary statistics for seven pain phenotypes. We identified 18 candidate genes [...] Read more.

The causal contributions of specific mitochondrial genes to common pain phenotypes remain unclear. We employed a multi-omics Mendelian randomization (SMR) approach, integrating QTL data (expression, methylation, protein) for mitochondrial genes with GWAS summary statistics for seven pain phenotypes. We identified 18 candidate genes with robust SMR associations across omics layers. However, strong colocalization evidence (PP.H4 > 0.7) was largely absent, pointing towards complex genetic architectures. A notable exception was a strong signal for a shared causal variant found at the methylation level for the MCL1 gene in hip pain (PP.H4 = 0.962), nominating it as a high-confidence candidate. Additionally, genetically predicted higher protein levels of Glycine amidinotransferase (GATM) showed consistent protective associations with neck or shoulder, back, and knee pain. This study provides novel evidence for mitochondrial gene regulation in pain, highlighting the GATM pathway as protective and identifying MCL1 methylation as a potential causal mechanism in hip pain. Full article

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

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23 pages, 4531 KB

Open AccessArticle

Examining the Roles of Genomic Context and Endogenous Regulatory Elements on IS1 Transposition Within the Escherichia coli Genome

by Sofia Smith, Zhongge Zhang, Allyson Ho, Tusha Karnani, Jack Ord and Milton H. Saier, Jr.

Int. J. Mol. Sci. 2025, 26(17), 8375; https://doi.org/10.3390/ijms26178375 - 28 Aug 2025

Cited by 1 | Viewed by 1958

Abstract

Insertion sequence (IS) elements are key drivers of bacterial genome plasticity, yet the overall regulation of their transposition remains poorly understood. This is especially true for the multiple-layer regulation at the donor site, which has been largely overlooked. Using multiple mutation assays, genetic [...] Read more.

Insertion sequence (IS) elements are key drivers of bacterial genome plasticity, yet the overall regulation of their transposition remains poorly understood. This is especially true for the multiple-layer regulation at the donor site, which has been largely overlooked. Using multiple mutation assays, genetic manipulations and reporter genes, this study focuses on characterizing how endogenous DNA sequences, transcriptional and translational factors, and genomic context regulate IS1 transposition from its donor site. Out of six elements within the chromosome of E. coli strain BW25113, IS1A and IS1E (both with the consensus sequence) contribute to over 99.9% of the overall IS1 transposition within the genome while the other four elements without the non-consensus sequence are essentially incapable of transposing. Inducing a ribosomal -1 frameshift at the A₆C motif increases transposition over 1000-fold, but this enhancement is largely reversed by restoring InsA-mediated transcriptional regulation. Strikingly, genomic sequences flanking IS1 elements appreciably modulate transposition by promoting transcription or facilitating formation of transpososomes, a phenomenon that remains under-studied. Finally, IS1 was confirmed to undergo replicative transposition intramolecularly, a mechanism shown here to be independent of transposase levels in the cell. These findings contribute to our understanding of mobile genetic element regulation and potentially offer strategies for mitigating their potentially harmful effects. Full article

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

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Review

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36 pages, 3635 KB

Open AccessReview

Integrated Symbiotic Pleiotropy: Long Non-Coding RNAs and Disordered Proteins Interweaving the Functional Layers of the Eukaryotic Cell

by Evelina Daskalova, Joon Seon Lee, Gergana Zahmanova and Ivan Minkov

Int. J. Mol. Sci. 2026, 27(8), 3478; https://doi.org/10.3390/ijms27083478 - 13 Apr 2026

Abstract

Long non-coding RNAs (lncRNAs) and RNA–protein complexes (RNPs) are increasingly recognized as central to the regulatory complexity of modern eukaryotes. This review proposes that the remarkable diversity of eukaryotic systems arises from the long-term integration of ancient RNA/RNP mechanisms, layered with innovations introduced [...] Read more.

Long non-coding RNAs (lncRNAs) and RNA–protein complexes (RNPs) are increasingly recognized as central to the regulatory complexity of modern eukaryotes. This review proposes that the remarkable diversity of eukaryotic systems arises from the long-term integration of ancient RNA/RNP mechanisms, layered with innovations introduced by successive symbioses. We outline four interconnected levels of symbiosis contributing to this process: (1) molecular symbiosis, involving dynamic assemblies of RNAs, proteins, and membraneless organelles (MLOs); (2) genome symbiosis, driven by the expansion of non-coding and repetitive DNA; (3) intracellular symbiosis, initiated by mitochondria acquisition; and (4) intercellular symbiosis, rooted in the cellular cooperation that enables multicellularity. We highlight lncRNAs and intrinsically disordered proteins (IDPs) as versatile mediators that interweave interactions across scales, predominantly within phase-separated condensates. Building upon these multi-level processes, we propose the framework of integrated symbiotic pleiotropy—a concept where molecular components acquire layered functional roles as a direct consequence of successive symbiotic acquisitions. This paradigm unites information layering, functional moonlighting, molecular tinkering, and exaptation into a coherent trajectory for eukaryotic evolution. Full article

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

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54 pages, 3951 KB

Open AccessReview

Conserved Pathways, Divergent Outcomes: A Cross-Species Genomic Perspective on the Cancer–Neurodegeneration Paradox

by Bhargavi Rajarathinam, Durga Nandan, Parvathy Venugopal, Amritha M. Nair, Subin John, Bipin G. Nair and Rajaguru Aradhya

Int. J. Mol. Sci. 2026, 27(7), 2989; https://doi.org/10.3390/ijms27072989 - 25 Mar 2026

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Abstract

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the [...] Read more.

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune–stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons. Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration. Full article

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

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24 pages, 684 KB

Open AccessReview

Anti-Inflammatory Diets in Metabolic Syndrome and Obesity: Multi-Omics Perspectives on the Interplay Between Gut Microbiota, DNA Methylation, and Adipokine Regulation—A Narrative Review

by Karol Makiel

Int. J. Mol. Sci. 2026, 27(6), 2734; https://doi.org/10.3390/ijms27062734 - 17 Mar 2026

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Abstract

An anti-inflammatory dietary pattern represents a key component of non-pharmacological management in obesity and metabolic syndrome (MetS), as it targets chronic low-grade inflammation, adipose tissue dysfunction, insulin resistance, and disturbances of the gut–metabolic axis. In the present work, we outline a framework for [...] Read more.

An anti-inflammatory dietary pattern represents a key component of non-pharmacological management in obesity and metabolic syndrome (MetS), as it targets chronic low-grade inflammation, adipose tissue dysfunction, insulin resistance, and disturbances of the gut–metabolic axis. In the present work, we outline a framework for an “omics-based” approach that integrates data on gut microbiota composition and function (metagenomics), adipokine profiles, nutrigenomics, epigenetics, and related transcriptomic and metabolomic layers in order to enable more precise characterization of the metabolic phenotype and to support precision nutrition strategies. The proposed dietary model emphasizes the quality rather than merely the quantity of macronutrients, with particular focus on lipid profile optimization. Specifically, total fat intake is recommended to remain below 30% of total energy through the reduction in saturated fatty acids (SFA), trans fats, and excessive omega-6 fatty acids, alongside increased consumption of omega-3 PUFA (EPA/DHA) and plant-based sources of α-linolenic acid (ALA). Concurrently, greater intake of lean protein sources and low-glycemic-index carbohydrates rich in dietary fibre—particularly fermentable fractions—is recommended. The model also highlights the importance of polyphenols with antioxidant and immunomodulatory properties. To enhance feasibility and long-term adherence, recommendations are structured as flexible food substitutions rather than rigid prescriptions. Further well-designed interventional studies are required to confirm the impact of a multi-omics-based anti-inflammatory diet on both molecular and clinical endpoints. Full article

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

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15 pages, 1108 KB

Open AccessReview

A Translational Roadmap for Neurological Nonsense Mutation Disorders

by Jiaqing Li, Zhenyun Zhu and Sanqing Xu

Int. J. Mol. Sci. 2026, 27(3), 1418; https://doi.org/10.3390/ijms27031418 - 30 Jan 2026

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Abstract

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal [...] Read more.

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal muscular atrophy, Rett syndrome, and Duchenne muscular dystrophy. Readthrough therapies—strategies to override PTCs and restore full-length protein expression—have evolved from early aminoglycosides to modern precision tools including suppressor tRNAs, RNA editing, and CRISPR-based platforms. Yet clinical translation remains hampered by inefficient CNS delivery, variable efficacy, and the absence of personalized stratification. In this review, we propose a translational framework—the 4 Ds of Readthrough Therapy—to systematically address these barriers. The framework dissects the pipeline into Detection (precision patient identification and biomarker profiling), Delivery (engineered vectors for CNS targeting), Decoding (context-aware molecular correction), and Durability (long-term safety and efficacy). By integrating advances in machine learning, nanocarriers, base editing, and adaptive trial designs, this roadmap provides a structured strategy to bridge the translational gap. We advocate that a synergistic, modality-tailored approach will transform nonsense suppression from palliative care to durable, precision-based cures for once-untreatable neurological disorders. Full article

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

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29 pages, 2053 KB

Open AccessReview

Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics

by Eva Bagyinszky and Seong Soo A. An

Int. J. Mol. Sci. 2025, 26(20), 9960; https://doi.org/10.3390/ijms26209960 - 13 Oct 2025

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Abstract

Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer’s disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN [...] Read more.

Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer’s disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN was a multifunctional protein involved in lysosomal function, neuroinflammation, and neuronal survival. This review discusses the contributions of GRN haploinsufficiency to FTD pathogenesis with an emphasis on genetic mutations, downstream cellular consequences, relevant animal and cellular models, and emerging therapeutic strategies. Loss-of-function mutations in GRN were responsible up to ~50% reduction in PGRN levels, resulting in lysosomal dysfunction, TDP-43 aggregation, impaired microglial homeostasis, and enhanced neuroinflammation. Multiple in vitro and in vivo models recapitulated these pathological features. Novel therapeutic approaches, such as AAV-mediated gene therapy, stop codon readthrough compounds, SORT1 inhibitors, and antisense oligonucleotides, were investigated to restore PGRN levels and to mitigate disease progressions. However, challenges included the oncogenic risks of overexpression and the limited translational success in clinical trials to date. Targeting GRN haploinsufficiency became a promising avenue for FTD therapy. Improved models and refined delivery systems would be essential to develop safe and effective treatments. Future work should also focus on biomarker-guided interventions in presymptomatic mutation carriers. Full article

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

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