International Journal of Molecular Sciences

12 pages, 1732 KB

Open AccessArticle

Post-Translational Changes in Serum Albumin in Patients with Alcohol-Associated Hepatitis

by Jonathan Montomoli, Maurizio Baldassarre, Thomas Damgaard Sandahl, Marina Naldi, Emilie Glavind, Enrico Pompili, Peter Jepsen, Francesco Palmese, Paolo Caraceni, Hendrik Vilstrup and Marco Domenicali

Int. J. Mol. Sci. 2026, 27(3), 1503; https://doi.org/10.3390/ijms27031503 (registering DOI) - 3 Feb 2026

Abstract

Post-translational modifications of human serum albumin (HSA) have been described in patients with liver disease. This prospective cohort study aimed to characterize HSA microheterogeneity in hospitalized patients with alcohol-associated hepatitis (AH) and investigate its clinical relevance. We analyzed HSA isoforms by mass spectrometry [...] Read more.

Post-translational modifications of human serum albumin (HSA) have been described in patients with liver disease. This prospective cohort study aimed to characterize HSA microheterogeneity in hospitalized patients with alcohol-associated hepatitis (AH) and investigate its clinical relevance. We analyzed HSA isoforms by mass spectrometry in 49 patients with AH (at admission and day 14) and 20 healthy controls. Survival at 30, 90, and 365 days was assessed. Differences in HSA isoform abundance were compared between controls and AH patients, as well as between 90-day survivors and non-survivors. AH patients (69% male, median age 53 years) exhibited a significantly different HSA form profile compared to controls, with a lower amount of native HSA and higher oxidized forms. Native HSA negatively correlated with total HSA concentration (R = −0.47, p < 0.001). The relative amount of native HSA increased non-significantly from admission to day 14, but its estimated concentration increased significantly (8.8 vs. 12.0 g/L, p = 0.005). There were no significant differences in HSA forms between 90-day survivors and non-survivors at admission or day 14. Patients with AH exhibit extensive post-translational modifications of HSA compared to healthy individuals. While HSA forms changed during early hospitalization, they did not significantly correlate with short-term mortality in this cohort. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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23 pages, 13805 KB

Open AccessArticle

Systemic Inflammation Aggravates Retinal Ganglion Cell Vulnerability to Optic Nerve Trauma in Adult Rats

by Giuseppe Rovere, Yolanda Caja-Matas, Beatriz Vidal-Villegas, José M. Bernal-Garro, Paloma Sobrado-Calvo, Manuel Salinas-Navarro, Carlo Nucci, María Paz Villegas-Pérez, Manuel Vidal-Sanz, Marta Agudo-Barriuso and Francisco M. Nadal-Nicolás

Int. J. Mol. Sci. 2026, 27(3), 1502; https://doi.org/10.3390/ijms27031502 (registering DOI) - 3 Feb 2026

Abstract

Systemic inflammation is increasingly recognized as a modifier of neurodegenerative outcomes in the central nervous system; however, its impact on retinal ganglion cell (RGC) survival and retinal microglial responses following optic nerve (ON) injury in vivo remains incompletely understood. In this study, we [...] Read more.

Systemic inflammation is increasingly recognized as a modifier of neurodegenerative outcomes in the central nervous system; however, its impact on retinal ganglion cell (RGC) survival and retinal microglial responses following optic nerve (ON) injury in vivo remains incompletely understood. In this study, we investigated how systemic lipopolysaccharide (LPS)-induced inflammation influences retinal microglial activation and RGC vulnerability under physiological conditions and after traumatic ON damage. In adult female rats, systemic LPS administration by intraperitoneal injection induced rapid and robust microglial activation, characterized by process retraction and soma hypertrophy within hours and promoting microglial proliferation at later stages but without causing RGC loss in intact retinas. Following ON crush, systemic inflammation did not affect early RGC degeneration but significantly exacerbated neuronal loss during the late acute phase. This increased vulnerability was accompanied by a marked rise in microglial density and a pronounced redistribution of microglia toward the central retina and the ON head, a region of heightened anatomical and metabolic susceptibility. Together, these findings demonstrate that, in rats, systemic inflammation alone is insufficient to induce RGC degeneration but acts as a potent priming factor that amplifies neurodegeneration in the context of axonal injury. The temporal and spatial specificity of microglial responses underscores their context-dependent role in retinal pathology and identifies systemic inflammatory status as a critical determinant of retinal outcome after trauma. Targeted, time-dependent modulation of microglial activation may therefore represent a promising therapeutic strategy for optic neuropathies. Full article

(This article belongs to the Special Issue Signaling Pathways in Neuroinflammation or Neurodegenerative Disorders)

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17 pages, 6597 KB

Open AccessArticle

Sexual Dimorphism in the Initial Apoptotic Switch During MASH Progression in Mice

by Pradeep K. Rajan, Jacqueline A. Sanabria, Mathew S. Schade, Utibe-Abasi S. Udoh, Alexei Gorka, Sodhi Komal, Sandrine V. Pierre and Juan Sanabria

Int. J. Mol. Sci. 2026, 27(3), 1501; https://doi.org/10.3390/ijms27031501 (registering DOI) - 3 Feb 2026

Abstract

MASH is a progressive liver disease closely associated with cellular senescence, which is present in more than 80% of hepatocytes in patients who develop hepatocellular carcinoma (HCC). Although MASH affects both sexes, the incidence of MASH-related HCC is two to four times higher [...] Read more.

MASH is a progressive liver disease closely associated with cellular senescence, which is present in more than 80% of hepatocytes in patients who develop hepatocellular carcinoma (HCC). Although MASH affects both sexes, the incidence of MASH-related HCC is two to four times higher in males. Our group has previously described two apoptotic switches during MASH progression and HCC development, implicating the ATP1A1 signalosome in the late switch. Here, we investigated the role of ATP1A1 and sex-specific differences in the early apoptotic switch during preclinical MASH progression. Male and female C57BL/6J mice (7 weeks old) were fed normal mouse chow (NMC) or a high-fat diet (HFD) for 12, 24, or 48 weeks (n = 5/sex/group). Total body weight (TBW) and body composition were assessed by serial measurement and echo-MRI. Plasma was analyzed by non-targeted metabolomics and glutathione profiling using LC-MS/MS. NAFLD activity scores (NAS), hepatic senescence, and apoptosis were quantified in liver tissue. Statistical analyses were performed using GraphPad Prism and R. Males gained greater TBW and lean and fat mass than females (p < 0.05). At 24 W, males demonstrated higher GSH:GSSG ratios and lower ophthalmate levels than females (p < 0.05), consistent with altered redox balance. HFD-fed females showed increased succinic and deoxycholic acid levels, whereas males exhibited higher butyric acid levels across all time points (p < 0.05). Males had a higher mTOR 1 expression at 24 W and pT53 at 12 W compared to females on HFD, but a lower Grb2 expression at 24 W (p < 0.05). By 24 W, males had lower fibrosis scores and reduced apoptotic activity compared with females (p < 0.05), despite similar levels of cellular senescence. The expression of ATP1A1, survivin, and SMAC did not differ by sex or diet, although an upregulation trend in both ATP1A1 and survivin was noted in the male-HFD group. There is sexual dimorphism in the response to HFD during the transition from senescence to the apoptosis-first apoptotic switch in MASH progression. Full article

(This article belongs to the Special Issue The Na, K-ATPase in Health and Disease)

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6 pages, 536 KB

Open AccessEditorial

Special Issue: “Molecular Mechanisms and Regulation in Chronic Kidney Diseases”

by Charlotte Delrue, Joris R. Delanghe and Marijn M. Speeckaert

Int. J. Mol. Sci. 2026, 27(3), 1500; https://doi.org/10.3390/ijms27031500 - 3 Feb 2026

Abstract

Chronic kidney disease (CKD) has become one of the most important medical challenges today, affecting approximately 850 million people worldwide [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Chronic Kidney Diseases)

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57 pages, 5969 KB

Open AccessArticle

Bioinformatic Analyses of the Ataxin-2 Family Since Algae Emphasize Its Small Isoforms, Large Chimerisms, and the Importance of Human Exon 1B as Target of Therapies to Prevent Neurodegeneration

by Georg W. J. Auburger, Jana Key, Suzana Gispert, Isabel Lastres-Becker, Luis-Enrique Almaguer-Mederos, Carole Bassa, Antonius Auburger, Georg Auburger, Aleksandar Arsovic, Thomas Deller and Nesli-Ece Sen

Int. J. Mol. Sci. 2026, 27(3), 1499; https://doi.org/10.3390/ijms27031499 - 3 Feb 2026

Abstract

Polyglutamine expansion in Ataxin-2 (ATXN2) is responsible for rare, dominantly inherited Spinocerebellar Ataxia type 2 (SCA2). Together with its paralog Ataxin-2-like (ATXN2L), both proteins have received much interest, since the deletion of their yeast and fly orthologs alleviates TDP-43-triggered neurotoxicity in Amyotrophic Lateral [...] Read more.

Polyglutamine expansion in Ataxin-2 (ATXN2) is responsible for rare, dominantly inherited Spinocerebellar Ataxia type 2 (SCA2). Together with its paralog Ataxin-2-like (ATXN2L), both proteins have received much interest, since the deletion of their yeast and fly orthologs alleviates TDP-43-triggered neurotoxicity in Amyotrophic Lateral Sclerosis models. Their typical structure across evolution combines LSm with LSm-Associated Domains and a PAM2 motif. To understand the physiological regulation and functions of Ataxin-2 homologs, the phylogenesis of sequences was analyzed. Human ATXN2 harbors multiple alternative start codons, e.g., from an intrinsically disordered sequence (IDR) present since armadillo, or from the polyQ sequence that arose since amphibians, or from the LSm domain since primitive eukaryotes. Multiple smaller isoforms also exist across the C-terminus. Therapeutic knockdown of polyQ expansions in human ATXN2 should selectively target exon 1B. PolyQ repeats developed repeatedly, usually framed and often interrupted by (poly)Pro, originally near PAM2. The LSmAD sequence appeared in algae as the characteristic Ataxin-2 feature with strong conservation. Frequently, Ataxin-2 has added domains, likely due to transcriptional readthrough of neighbor genes during cell stress. These chimerisms show enrichment of rRNA processing; nutrient store mobilization; membrane strengthening via lipid, protein, and glycosylated components; and cell protrusions. Thus, any mutation of Ataxin-2 has complex effects, also affecting membrane resilience. Full article

(This article belongs to the Special Issue Molecular Research on Ataxia)

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15 pages, 3603 KB

Open AccessArticle

Atrial Fibrillation and Primary Cilia-Associated Genes: The Role of CEP68

by Zhenyu Dong, Rushd F. M. Al-Shama, Nicoline W. E. van den Berg, Makiri Kawasaki, Marc M. Terpstra, Nerea Arrarte Terreros, Elise L. Hulsman, Aldo Jongejan, Rishi A. Arora, Wim Jan P. van Boven, Antoine H. G. Driessen, Connie R. Bezzina, Sean J. Jurgens and Joris R. de Groot

Int. J. Mol. Sci. 2026, 27(3), 1498; https://doi.org/10.3390/ijms27031498 - 3 Feb 2026

Abstract

Recent studies have demonstrated that primary cilia not only play a role in cardiovascular development, but also in the progression of acquired heart disease. Their role in atrial fibrillation (AF) is incompletely understood. We hypothesize that there is a causal link between primary [...] Read more.

Recent studies have demonstrated that primary cilia not only play a role in cardiovascular development, but also in the progression of acquired heart disease. Their role in atrial fibrillation (AF) is incompletely understood. We hypothesize that there is a causal link between primary cilia genes and the occurrence of AF. We integrated AF GWAS data with various multi-omic datasets—including data on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL)—from human left atrial appendage (LAA) tissues and blood. Genetic variants linked to primary cilia-related genes were used as instrumental variables to explore their causal links to AF, through summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Single-cell sequencing data were used to analyze the expression of the selected genes across different cell types. The mechanisms by which the selected genes exert their effects were explored using RNA sequencing data, clinical indicators, and immunohistochemical markers from 22 patients without AF from the PREDICT-AF cohort, and 21 patients with paroxysmal AF and 19 patients with persistent AF from the MARK-AF cohort. Through SMR analyses, we established significant associations between predicted CEP68 expression and AF in both blood (OR 1.25; 95% CI 1.18–1.33; false discovery rate (FDR) = 1.81 × 10⁻⁹) and LAA tissue (OR 1.12; 95% CI 1.08–1.16; FDR = 6.18 × 10⁻⁹). Moreover, predicted methylation of CEP68 showed an inverse relationship with AF risk (OR 0.87; 95% CI 0.84–0.90; FDR = 2.55 × 10⁻¹⁵). Colocalization results for CEP68 in both blood and the LAA indicated strong evidence of a shared causal variant. Within single-cell data, compared to the control group, AF patients had higher levels of CEP68 in fibroblasts (p = 0.046). In bulk RNA-seq data, CEP68 expression showed no significant differences among the no AF, paroxysmal AF, and persistent AF groups. CEP68 was positively correlated with the cardiac remodeling marker Thrombospondin-2 in 22 patients without AF from the PREDICT-AF cohort (r = 0.45, p = 0.03). In AF patients from the MARK-AF study, CEP68 was also positively associated with LAVI (r = 0.34, p = 0.03). Collectively, our results support a model in which genetically predicted CEP68 regulation is linked to AF liability and is consistent with fibroblast activation and remodeling-related pathways as potential mediators. Full article

(This article belongs to the Special Issue Functional (Pharmaco) Genomics and Genetics in Atrial Fibrillation Associated with Sudden Cardiac Death Syndromes)

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12 pages, 359 KB

Open AccessArticle

Detection of TERT Promoter Mutations in Papillary Thyroid Carcinoma Using Droplet Digital PCR and Their Association with Aggressive Tumor Features

by Jeongmin Lee, Chaiho Jeong, Jeonghoon Ha, Dong-Jun Lim, Tae-Jung Kim and Ki-Hyun Baek

Int. J. Mol. Sci. 2026, 27(3), 1497; https://doi.org/10.3390/ijms27031497 - 3 Feb 2026

Abstract

This study evaluated the reliability of droplet digital polymerase chain reaction (ddPCR) for detecting TERT promoter (pTERT) mutations in formalin-fixed, paraffin-embedded (FFPE) thyroid cancer samples and examined their association with clinicopathological features. A retrospective cohort of 296 postoperative patients with papillary thyroid carcinoma [...] Read more.

This study evaluated the reliability of droplet digital polymerase chain reaction (ddPCR) for detecting TERT promoter (pTERT) mutations in formalin-fixed, paraffin-embedded (FFPE) thyroid cancer samples and examined their association with clinicopathological features. A retrospective cohort of 296 postoperative patients with papillary thyroid carcinoma (PTC) was analyzed. DNA extracted from archived FFPE thyroidectomy specimens was examined for TERT promoter mutations using ddPCR. pTERT mutations were detected in 14 cases (4.7%). Tumors harboring pTERT mutations were significantly larger than wild-type tumors (1.5 ± 1.3 cm vs. 1.0 ± 0.7 cm, p = 0.012) and showed higher frequencies of extrathyroidal extension (78.6% vs. 55.0%, p = 0.028), capsular invasion (85.7% vs. 63.1%, p = 0.036), and lymph node metastasis (64.3% vs. 44.0%, p = 0.012). Multivariate analysis demonstrated that increasing age (odds ratio (OR), 1.07; 95% confidence interval (CI), 1.01–1.13; p = 0.015), tumor size (OR, 1.86; 95% CI, 1.12–3.08; p = 0.016), and lymph node metastasis (OR, 3.50; 95% CI, 1.09–6.53; p = 0.026) were independently associated with pTERT mutations. ddPCR enables sensitive detection of pTERT mutations in archived FFPE thyroid cancer specimens and identifies tumors with aggressive clinicopathological features, supporting its utility for postoperative risk stratification in clinical practice. Full article

(This article belongs to the Special Issue Thyroid-Related Diseases: Molecular Pathology, Diagnosis and Treatment: 2nd Edition)

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16 pages, 2627 KB

Open AccessArticle

Single-Cell Mapping Reveals MIF-Centered Immunoregulatory Networks in Colorectal Cancer

by Marios Gkoris, Ilias Georgakopoulos-Soares and Apostolos Zaravinos

Int. J. Mol. Sci. 2026, 27(3), 1496; https://doi.org/10.3390/ijms27031496 - 3 Feb 2026

Abstract

Colorectal cancer (CRC) progression is strongly shaped by the tumor microenvironment (TME), where complex interactions between epithelial, immune, and stromal cells orchestrate immune suppression and tumor evolution. To dissect these relationships at single-cell resolution, we analyzed CRC scRNA-seq datasets using Seurat for data [...] Read more.

Colorectal cancer (CRC) progression is strongly shaped by the tumor microenvironment (TME), where complex interactions between epithelial, immune, and stromal cells orchestrate immune suppression and tumor evolution. To dissect these relationships at single-cell resolution, we analyzed CRC scRNA-seq datasets using Seurat for data integration and CellChat for ligand–receptor inference. We identified extensive cellular heterogeneity within the TME, dominated by CMS2/CMS3 epithelial states, SPP1⁺ tumor-associated macrophages, diverse T-cell subsets, and CXCR4⁺ B cells. Communication analysis revealed MIF-centered signaling—including MIF–CD74–CXCR4 and MIF–CD74–CD44—as the predominant axis linking tumor epithelial cells with T cells, B cells, and macrophage subpopulations. CMS3 epithelial cells displayed particularly strong connectivity to SPP1⁺ macrophages and cytotoxic lymphocytes through both MIF- and APP–CD74-mediated pathways. Differential gene expression confirmed elevated levels of MIF, CD74, CD44, and SPP1 in tumor tissues, while pathway enrichment analyses highlighted cytokine signaling, antigen presentation, and chemokine-regulated immune modulation as key biological processes. Collectively, our study provides a high-resolution map of CRC intercellular communication and identifies MIF-CD74-associated signaling as a central immunoregulatory hub with potential relevance for therapeutic targeting and biomarker development. Full article

(This article belongs to the Special Issue Colorectal Cancers: New Approach to Their Pathology, Diagnosis and Therapy)

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34 pages, 7277 KB

Open AccessReview

Unlocking the Secrets of Regulated Cell Death in Large B-Cell Lymphoma Beyond Apoptosis: Signaling Pathways and Therapeutic Options

by Anton Tkachenko and Ondrej Havranek

Int. J. Mol. Sci. 2026, 27(3), 1495; https://doi.org/10.3390/ijms27031495 - 3 Feb 2026

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell type of non-Hodgkin’s lymphoma. Recent genomic studies have highlighted the importance of genetic alterations in apoptotic pathways that help malignant DLBCL cells to evade apoptosis. Apoptosis evasion by DLBCL cells is known to [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell type of non-Hodgkin’s lymphoma. Recent genomic studies have highlighted the importance of genetic alterations in apoptotic pathways that help malignant DLBCL cells to evade apoptosis. Apoptosis evasion by DLBCL cells is known to mediate resistance to chemotherapy. Advances in the field of regulated cell death (RCD) research have identified novel therapeutic avenues in cancer. In particular, non-apoptotic RCDs can be targeted to overcome resistance to apoptosis in cancer and ensure cell death. In this review, we have highlighted the contribution of multiple RCDs, including apoptosis, necroptosis, ferroptosis, pyroptosis, PANoptosis, NETotic cell death, autophagy-dependent cell death, cuproptosis, methuosis, or mitotic death, to normal development of B lymphocytes and DLBCL pathogenesis. We have summarized molecular mechanisms governing distinct RCDs in DLBCL, differences in cell death pathways in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL subtypes, prognostic values of RCD-related genes, and discussed the implication of RCD pathways for DLBCL treatment. Notably, the impact of RCDs goes far beyond just killing tumor cells. RCD modalities are important for orchestrating the immune response and modulating the tumor microenvironment. The current review also aims to reveal the effect of different RCDs on the tumor microenvironment in DLBCL. Most RCDs play a dual role in DLBCL, demonstrating both tumor-inducing and tumor-suppressing effects, which suggests that their targeting should be exploited with caution. Our analysis suggests that pharmacological ferroptosis induction may be the most promising RCD-targeting strategy in DLBCL. Full article

(This article belongs to the Special Issue Advancements in Hematology: Molecular Biology and Targeted Therapies)

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24 pages, 7327 KB

Open AccessArticle

Dual Immunological Prognostic Models for Risk Stratification and Treatment Insights in Triple-Negative Breast Cancer

by Shihua Lin, Hongjiu Wang, Zhenzhen Wang, Yuxuan Xiao, Menoudji Djetoyom Patrice, Li Wang, Xia Li and Yunpeng Zhang

Int. J. Mol. Sci. 2026, 27(3), 1494; https://doi.org/10.3390/ijms27031494 - 3 Feb 2026

Abstract

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, with its highly heterogeneous tumor microenvironment posing substantial challenges for precision diagnosis and therapy. To address this, we aim to construct a novel prognostic framework based on tumor-immune interactions. Through integrative analysis [...] Read more.

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, with its highly heterogeneous tumor microenvironment posing substantial challenges for precision diagnosis and therapy. To address this, we aim to construct a novel prognostic framework based on tumor-immune interactions. Through integrative analysis of single-cell RNA sequencing data from 30 TNBC samples (106,132 cells), we identify key tumor expression metaprograms and uncover their interaction with an immunosuppressive dendritic-cell subset, a process associated with the NECTIN1–NECTIN4 axis. Leveraging these interactions, we developed and validated two immunological prognostic models using multi-cohort transcriptomic data, including the stress response tumor cell and pDC_CLEC4C prognostic model (SPSM) and the immune response tumor cell and pDC_CLEC4C prognostic model (IPSM). These models effectively stratified TNBC patients into distinct risk groups, with the low-risk group characterized by an immunologically active microenvironment and elevated expression of immune checkpoint genes, suggesting a potential responsiveness to immunotherapy. Furthermore, we identified several potential therapeutic agents, including imatinib and bortezomib. Collectively, our dual-model framework provides a tool for risk stratification, offers translational insights for precision treatment, and presents new directions for understanding TNBC heterogeneity and therapeutic development. Full article

(This article belongs to the Special Issue Molecular Research in Triple-Negative Breast Cancer: 2nd Edition)

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17 pages, 553 KB

Open AccessReview

Targeted RNA Degradation by RIBOTACs: A Novel Therapeutic Avenue for Ophthalmic Diseases

by Dario Rusciano, Caterina Gagliano, Alessandro Avitabile and José Fernando Maya-Vetencourt

Int. J. Mol. Sci. 2026, 27(3), 1493; https://doi.org/10.3390/ijms27031493 - 3 Feb 2026

Abstract

Ophthalmic diseases, including inherited retinal dystrophies, age-related macular degeneration (AMD), and glaucomatous neuropathies, are often driven by the expression of pathogenic proteins or dysfunctional non-coding RNAs that are currently considered ‘undruggable’ with conventional small-molecule therapeutics. The emerging strategy of Ribonuclease-Targeting Chimeras (RIBOTACs) offers [...] Read more.

Ophthalmic diseases, including inherited retinal dystrophies, age-related macular degeneration (AMD), and glaucomatous neuropathies, are often driven by the expression of pathogenic proteins or dysfunctional non-coding RNAs that are currently considered ‘undruggable’ with conventional small-molecule therapeutics. The emerging strategy of Ribonuclease-Targeting Chimeras (RIBOTACs) offers a revolutionary approach to address this therapeutic gap. RIBOTACs are heterobifunctional small molecules designed to bind a specific target RNA with one moiety and recruit a latent endogenous ribonuclease, such as RNase L, with the other, thereby catalyzing the RNA’s degradation. This targeted degradation can potentially halt the production of mutant proteins, eliminate toxic gain-of-function RNAs, or modulate key regulatory pathways involved in angiogenesis, inflammation, and apoptosis—core processes in many blinding diseases. This review explores the immense potential of applying RIBOTAC technology to ophthalmology, discussing prospective targets such as mutant alleles in retinitis pigmentosa, VEGF transcripts in neovascular AMD, and inflammatory mediators in uveitis. We will also address the unique challenges and opportunities for RIBOTAC development in the eye, including delivery strategies to overcome ocular barriers, the need for high specificity to avoid off-target RNA degradation, and the optimization of pharmacokinetic properties for intraocular administration. With continued innovation, RIBOTACs are poised to evolve into a robust therapeutic platform, expanding the druggable genome and enabling precise, durable treatments for a range of currently intractable ophthalmic conditions. Full article

(This article belongs to the Special Issue Recent Advances in RNA Drug Development)

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19 pages, 3991 KB

Open AccessArticle

Altered Microglia-Neuron Crosstalk and Regional Heterogeneity in Alzheimer’s Disease Revealed by Single-Nucleus RNA Sequencing

by Zhenqi Yang, Mingzhao Zhang, Weijia Zhi, Lizhen Ma, Xiangjun Hu, Yong Zou and Lifeng Wang

Int. J. Mol. Sci. 2026, 27(3), 1492; https://doi.org/10.3390/ijms27031492 - 3 Feb 2026

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60–70% of all clinically diagnosed cases worldwide. The growing focus on microglia–neuron interactions in AD [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60–70% of all clinically diagnosed cases worldwide. The growing focus on microglia–neuron interactions in AD research highlights their diverse, region-specific responses, which are driven by the functional and pathological heterogeneity across different brain regions. Therefore, investigating the interactions between microglia and neurons is of crucial importance. To explore the regional heterogeneity of microglia–neuron crosstalk in AD, we integrated human single-nucleus RNA sequencing data from the prefrontal cortex (PFC), hippocampus (HPC), and occipital lobe (OL) provided by the ssREAD database. Our study delineated four microglial subtypes and uncovered a pseudotime trajectory activation trajectory leading to the disease-associated microglia (DAM) phenotype. The transition along this trajectory is driven and stabilized by a key molecular switch: the coordinated downregulation of inhibitory factors (e.g., LINGO1) and upregulation of immune-effector and antigen-presentation programs, which collectively establish the pro-inflammatory DAM state. Furthermore, we observed that each brain region displayed unique microglia–neuron communication patterns in response to AD pathology. The PFC and OL engage a THY1-ITGAX/ITGB2 signaling axis; the HPC predominantly utilizes the PTPRM pathway. Notably, THY1 dysregulation strongly correlates with pathology in the PFC, HPC, and OL, suggesting that microglia–neuron crosstalk in AD possesses both heterogeneity and commonality. The main contribution of this study is the systematic characterization of region-specific microglia-neuron interactions and the identification of THY1 as a potential mediator that may be targeted therapeutically to modulate microglial function in affected brain regions. Full article

(This article belongs to the Special Issue Advancement of Understanding Alzheimer’s Disease Susceptibility and Novel Drug Targets)

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15 pages, 1241 KB

Open AccessArticle

by Sehime Gulsun Temel, Mustafa Samet Pir, Cuneyd Yavas, Feride I. Sahin, Sebnem Ozemri Sag and Yunus Kasim Terzi

Int. J. Mol. Sci. 2026, 27(3), 1491; https://doi.org/10.3390/ijms27031491 - 3 Feb 2026

Abstract

In genetic disease assessment centers, DNA sequencing can produce results irrelevant to the genetic examination’s purpose. The American College of Medical Genetics and Genomics (ACMG) recommends evaluating and reporting 81 genes discovered using clinical genomic sequencing. While population studies on large cohorts can [...] Read more.

In genetic disease assessment centers, DNA sequencing can produce results irrelevant to the genetic examination’s purpose. The American College of Medical Genetics and Genomics (ACMG) recommends evaluating and reporting 81 genes discovered using clinical genomic sequencing. While population studies on large cohorts can provide statistics on the prevalence of secondary findings (SFs), no studies have been published yet on large cohorts in Turkiye. We investigated ACMG SF by evaluating clinical exome sequencing data in 1600 individuals from different regions in Turkiye. We detected SF variants reported in ClinVar in 86 individuals (5.375%). Of the SFs, 30% were cardiovascular, 26% were cancer, 16% were neonatal metabolic disorders, and 28% were variants associated with various genetic diseases. In addition, we identified 212 different variants in 226 individuals and 45 different genes, which were not reported in ClinVar. When our results are compared with the Turkish National Genome and Bioinformatics Project database and studies in the literature, the studies vary in terms of participant characteristics, sequencing techniques, and versions of the ACMG SF list. Our findings highlight the importance of expanding and tailoring SF reporting guidelines in populations with high consanguinity and limited cohort-based data. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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14 pages, 286 KB

Open AccessReview

Glycomic Insights in Gynecological Disease: From Molecular Mechanisms to Precision Diagnostics and Therapeutics

by Róbert Pásztor and Csaba Váradi

Int. J. Mol. Sci. 2026, 27(3), 1490; https://doi.org/10.3390/ijms27031490 - 3 Feb 2026

Abstract

Gynecological diseases—encompassing polycystic ovary syndrome, endometriosis, infertility, and malignancies—represent a significant global health burden affecting women’s quality of life, reproductive capacity, and long-term health outcomes. While traditional diagnostics rely on protein-based biomarkers, clinical phenotyping, and imaging, these approaches often lack the sensitivity and [...] Read more.

Gynecological diseases—encompassing polycystic ovary syndrome, endometriosis, infertility, and malignancies—represent a significant global health burden affecting women’s quality of life, reproductive capacity, and long-term health outcomes. While traditional diagnostics rely on protein-based biomarkers, clinical phenotyping, and imaging, these approaches often lack the sensitivity and specificity required for early detection and personalized intervention. Glycomics, the comprehensive study of carbohydrate structures on proteins and lipids, represents an emerging molecular frontier in gynecological disease characterization and therapeutics. This review synthesizes current knowledge regarding glycomic dysregulation across gynecological conditions, elucidates how aberrant glycosylation patterns serve as disease-specific biomarkers, and demonstrates key translational applications, such as glycoform-specific CA-125. By integrating glycomics with complementary omics technologies and artificial intelligence-driven analysis, a transformative diagnostic paradigm is emerging that promises earlier detection, improved risk stratification, and precision-guided therapeutics for women with gynecological disorders. Full article

(This article belongs to the Special Issue Molecular Insights in Women’s Health: Advances in Gynecological Disease Mechanisms and Therapeutics)

19 pages, 4412 KB

Open AccessArticle

Targeted Lipidomics and Lipid Metabolism Elucidate Anti-Obesity Effects of Lactic Acid Bacteria-Fermented Purple Sweet Potato Tainung No. 73 Extract in Obese Mice

by Hsien-Yi Yang, Chien-Hsun Huang, Shang-Tse Ho, Hsin-Hui Su, Yen-Po Chen and Yung-Tsung Chen

Int. J. Mol. Sci. 2026, 27(3), 1489; https://doi.org/10.3390/ijms27031489 (registering DOI) - 3 Feb 2026

Abstract

The increasing prevalence of obesity and metabolic disorders poses a major global health challenge. In the present study, purple sweet potato Tainung No. 73 was fermented using Lactobacillus amylovorus OFMLa-73 and Levilactobacillus brevis OFMLb-143 to enrich the specific bioactive metabolite indolelactic acid. Furthermore, [...] Read more.

The increasing prevalence of obesity and metabolic disorders poses a major global health challenge. In the present study, purple sweet potato Tainung No. 73 was fermented using Lactobacillus amylovorus OFMLa-73 and Levilactobacillus brevis OFMLb-143 to enrich the specific bioactive metabolite indolelactic acid. Furthermore, supplementation with fermented sweet potato (FSPE) ethanol extract resulted in a significant reduction in body weight gain, adipocyte hypertrophy, and hepatic lipid accumulation, while also improving serum lipid profiles in high-fat diet-induced obesity mice. These physiological improvements were associated with the downregulated expression of adipogenic and inflammatory genes in both liver and adipose tissues. Furthermore, lipidomic analysis revealed that FSPE modulated key lipid species, including ceramides and acylcarnitines, which are implicated in metabolic dysfunction. Collectively, these findings demonstrated that lactic acid fermentation enhanced purple sweet potato’s functional potential, positioning FSPE as a promising candidate for dietary intervention in obesity management. Full article

(This article belongs to the Special Issue Role of Diet and Nutrition in Metabolic Diseases)

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19 pages, 1651 KB

Open AccessFeature PaperArticle

Dynamic microRNA Signatures as Biomarkers for Cardiac Ischemia and Remodeling

by Macarena Rodríguez-Serrano, Elena Martín-García, Patricia Alonso-Andrés, Elisa Conde-Moreno, Héctor Pian, Javier del Moral-Salmoral, Nunzio Alcharani, Miriam Menacho-Román, Lorena Crespo-Toro, Miren Edurne Ramos-Muñoz, Carlos Zaragoza, Luis Miguel Rincón, María G. Barderas and María Laura García-Bermejo

Int. J. Mol. Sci. 2026, 27(3), 1488; https://doi.org/10.3390/ijms27031488 - 3 Feb 2026

Abstract

Myocardial infarction (MI) triggers complex pathological processes, including inflammation, hypoxia, and fibrotic remodeling. MicroRNAs (miRNAs) have emerged as promising biomarkers for cardiovascular injury; however, their expression dynamics along processes remain underexplored. We used an in vivo rat model of permanent coronary occlusion to [...] Read more.

Myocardial infarction (MI) triggers complex pathological processes, including inflammation, hypoxia, and fibrotic remodeling. MicroRNAs (miRNAs) have emerged as promising biomarkers for cardiovascular injury; however, their expression dynamics along processes remain underexplored. We used an in vivo rat model of permanent coronary occlusion to study the molecular alterations associated with MI and its resolution in a temporal mode, including five experimental groups with five animals in each: sham, PO 24 h, PO 72 h, PO 7 d, PO 1 month. Histological analysis, serum biomarkers, and miRNA/gene expression profiles were analyzed in a time-dependent manner post-occlusion. Subsequent analysis revealed early depletion of selected circulating miRNAs (PO 24 h). Transient upregulation in cardiac tissue miRNAs, inflammatory and fibrotic gene expression (Fibronectin, Collagen, Vimentin, E-Cadherin) were observed at PO 72 h. These molecular alterations correlated with histological evidence of myocardial injury and repair. Taken together, our findings delineate the molecular timeline of MI progression and resolution and identify candidate miRNAs as sensitive and time-dependent indicators of myocardial stress, including miR-107, miR-122-5p and miR-221-3p. This integrative approach supports the use of miRNA signatures for noninvasive monitoring of cardiac injury and resolution and unveils potential therapeutic targets to reduce pathological remodeling. Full article

(This article belongs to the Special Issue MicroRNAs in Physiology and Pathophysiology)

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36 pages, 1084 KB

Open AccessReview

Nodule–Microbiome Dynamics: Deciphering the Complexities of Nodule Symbiosis and the Root Microbiome

by Raja Ben-Laouane, Mohamed Ait-El-Mokhtar, Abdelilah Meddich and Marouane Baslam

Int. J. Mol. Sci. 2026, 27(3), 1487; https://doi.org/10.3390/ijms27031487 - 2 Feb 2026

Abstract

Microbiomes play a pivotal role in sustaining plant function and broader ecosystem processes. Leguminous plants host vast populations of intracellular bacteria within specialized root organs known as nodules. The intricate mutualism between legumes and rhizobia ensures a stable supply of biologically fixed nitrogen [...] Read more.

Microbiomes play a pivotal role in sustaining plant function and broader ecosystem processes. Leguminous plants host vast populations of intracellular bacteria within specialized root organs known as nodules. The intricate mutualism between legumes and rhizobia ensures a stable supply of biologically fixed nitrogen (N) essential for plant growth. While rhizobia remain the central actors in this symbiosis, recent discoveries reveal the presence of non-rhizobial endophytes within nodules, suggesting a complex interplay shaped by host selection and compatibility with rhizobial partners. Understanding the structure and dynamics of crop nodule-associated microbial communities is thus critical for optimizing host responses to rhizobia and for leveraging beneficial plant–microbe interactions. This review explores the dualistic nature—both facilitative and inhibitory—of the nodule microbiome in relation to nodulation. We examine the diversity of soil bacteria that stimulate nodulation and those that ultimately colonize nodule tissues, questioning whether these functional groups overlap. Furthermore, we discuss the molecular dialogs and counter-signaling mechanisms that regulate endophyte ingress into nodules, and evaluate how nodule endophytes contribute to plant performance and soil fertility. Full article

(This article belongs to the Special Issue New Advances in Plant–Microbe Interaction)

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90 pages, 7461 KB

Open AccessPerspective

Therapeutic Options for Alzheimer’s Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm

by Vladimir Volloch and Sophia Rits-Volloch

Int. J. Mol. Sci. 2026, 27(3), 1486; https://doi.org/10.3390/ijms27031486 - 2 Feb 2026

Abstract

In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer’s disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies [...] Read more.

In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer’s disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies that AD can be initiated by any stressor capable of activating one or more of the four eIF2α kinases and accumulated intraneuronally to sufficient levels. In most instances of AD, such a stressor is intraneuronal Aβ (iAβ) accumulated to a PKR- and/or HRI-activating concentration and designated, in terms of the ACH2.0, as a “conventional stressor”. The ensuing disease is referred to, accordingly, as “conventional AD”. Any stressor other than iAβ, which is capable of activating one or more eIF2α kinases in neuronal cells, is designated as an “unconventional stressor”. At a sufficient concentration, it triggers elicitation of the neuronal ISR and initiates the disease, referred to in terms of the ACH2.0 as “unconventional AD”, at levels of iAβ below those required for activation of PKR and/or HRI. In both forms of AD, the neuronal ISR activates production of components essential for, and, consequently, enables operation of, the RNA-dependent mRNA amplification pathway. Human AβPP mRNA is eligible for this process, and its asymmetric amplification yields 5′-truncated mRNA molecules that are translated into C99 at rates that are orders of magnitude greater than those seen in AβPP proteolysis. The resulting C99 drives AD pathology; it also propagates the ISR state and perpetuates both its own production and the progression of the disease. Thus, the neuronal ISR-enabled amplification of AβPP mRNA constitutes the active core of AD. It follows that the essence of any effective therapy for AD, in both conventional and unconventional forms, is to either prevent activation or suppress the operation of the AβPP mRNA amplification process. The present perspective considers therapeutic options capable of accomplishing these objectives. They include inhibition of the neuronal ISR, targeted degradation of iAβ and C99, anti-antisense oligonucleotides (AASO) for AβPP RNA, and the restructuring of the 5′ terminus of AβPP mRNA. Collectively, these therapeutic approaches constitute the state of the art in the ACH2.0 paradigm; if successful, they would render both AD and aging-associated cognitive decline (AACD) obsolete. This study also describes transgenic animal and human neuronal cell-based models of both conventional and unconventional forms of AD that are suitable for testing the proposed therapeutic strategies. Full article

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

26 pages, 1241 KB

Open AccessReview

Reexamining the Role of Amyloid β Clearance from the Brain: Exporting Labile Iron from the Interstitial Fluid Performs a Protective Function

by Steven M. LeVine

Int. J. Mol. Sci. 2026, 27(3), 1485; https://doi.org/10.3390/ijms27031485 - 2 Feb 2026

Abstract

Advantageous functions have been attributed to amyloid β, which helps explain its expression despite a propensity to aggregate. Besides supporting cognitive processes, it has antimicrobial activity, e.g., amyloid β can entrap pathogens or disrupt their membranes. Since iron is an essential element for [...] Read more.

Advantageous functions have been attributed to amyloid β, which helps explain its expression despite a propensity to aggregate. Besides supporting cognitive processes, it has antimicrobial activity, e.g., amyloid β can entrap pathogens or disrupt their membranes. Since iron is an essential element for invading organisms, limiting its availability is an antimicrobial strategy. This can be achieved by various means, such as reducing circulating iron, as is the case for anemia of inflammation or anemia of chronic disease, which may occur in Alzheimer’s disease. The protein lactoferrin both sequesters iron and generates proteolytic fragments with antimicrobial properties, and amyloid β may have similar traits. Amyloid β, which is derived from proteolytic cleavage of amyloid precursor protein, directly inhibits microorganisms. In addition, it binds redox-active metals, such as iron and copper. After being generated, amyloid β can enter the interstitial fluid and undergo clearance by a variety of mechanisms (e.g., glymphatic system, transport across the blood–brain barrier, and uptake by microglia or astrocytes). This clearance, together with its small size and iron-binding properties, positions amyloid β to perform a surveillance function to access, capture, and export labile iron. By removing extraneous iron, amyloid β also helps to limit metal-catalyzed reactions that cause tissue damage. In summary, besides preventing the aggregation and neurotoxicity of amyloid β, the clearance of amyloid β from the CNS may serve a surveillance function to remove loosely bound iron to avert injury by redox reactions and enable amyloid β to function as a mammalian siderophore making iron unavailable to invading microorganisms. Full article

(This article belongs to the Collection 30th Anniversary of IJMS: Updates and Advances in Biochemistry)

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