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Functional Precision in Pancreatic Cancer: Redefining Biomarkers with Patient-Derived Organoids
Are Procoagulant Platelets an Emerging Therapeutic Target? A General Review with an Emphasis on Their Clinical Significance in Companion Animals
MASLD Under the Microscope: How microRNAs and Microbiota Shape Hepatic Metabolic Disease Progression
Sequencing Anti-CD19 Therapies in Diffuse Large B-Cell Lymphoma: From Mechanistic Insights to Clinical Strategies
Carbon Dots for Nucleic Acid-Based Diagnostics and Therapeutics: Focus on Oxidative DNA Damage

Journal Description

International Journal of Molecular Sciences

International Journal of Molecular Sciences is an international, peer-reviewed, open access journal providing an advanced forum for biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry, and is published semimonthly online by MDPI. The Australian Society of Plant Scientists (ASPS), Epigenetics Society, European Chitin Society (EUCHIS), Spanish Society for Cell Biology (SEBC) and others are affiliated with IJMS and their members receive a discount on the article processing charges.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, MEDLINE, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Biochemistry and Molecular Biology) / CiteScore - Q1 (Organic Chemistry)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 20.5 days after submission; acceptance to publication is undertaken in 2.6 days (median values for papers published in this journal in the first half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our editors and authors say about IJMS.
Companion journals for IJMS include: Biophysica, Stresses, Lymphatics and SynBio.

Impact Factor: 4.9 (2024); 5-Year Impact Factor: 5.7 (2024)

Imprint Information Journal Flyer Open Access ISSN: 1422-0067

Latest Articles

34 pages, 1389 KB

Open AccessReview

An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy

by Ekaterina Gornostal, Almaqdad Alsalloum, Egor Degtyarev, Ekaterina Kuznetsova, Aygun Levashova, Daria Mishina, Natalia Mingaleva, Ali Mazloum, Viktor Bogdanov, Julia Krupinova, Sergey Mikhalkov, Irina Rybkina, Olga Mityaeva and Pavel Volchkov

Int. J. Mol. Sci. 2025, 26(23), 11645; https://doi.org/10.3390/ijms262311645 (registering DOI) - 1 Dec 2025

X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus [...] Read more.

X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus (AAV)-based gene therapy for neurological manifestations of X-ALD. The development of a successful AAV-mediated gene therapy hinges on its ability to deliver ABCD1 cDNA effectively to the relevant organs and cell types, induce therapeutic levels of protein expression, and ultimately, restore normal very-long chain fatty acids (VLCFA) metabolic function. Thus, several key considerations should be addressed when designing AAV-based gene therapy for X-ALD, including the genetic background of the disease and requisite transgene expression levels, the biochemical function of the adrenoleukodystrophy protein (ALDP), the identification of target cells and their role in pathogenesis, the regulation of expression within the genetic construct, the route of administration, the selection of an AAV serotype with high tropism for the central and peripheral nervous systems, and the development of robust in vitro and in vivo models. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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17 pages, 2515 KB

Open AccessArticle

Potyvirus HcPro Suppressor of RNA Silencing Induces PVY Superinfection Exclusion in a Strain-Specific Manner

by Vincent N. Fondong and Prakash M. Niraula

Int. J. Mol. Sci. 2025, 26(23), 11644; https://doi.org/10.3390/ijms262311644 (registering DOI) - 1 Dec 2025

The potyvirus helper component proteinase (HcPro) is a multifunctional protein, with one of its most documented functions being host antiviral RNA silencing suppression. This study shows that the HcPro of potato virus Y (PVY), an important member of the potyvirus group, prevents the [...] Read more.

The potyvirus helper component proteinase (HcPro) is a multifunctional protein, with one of its most documented functions being host antiviral RNA silencing suppression. This study shows that the HcPro of potato virus Y (PVY), an important member of the potyvirus group, prevents the replication of a related competing secondary virus. This phenomenon, referred to as superinfection exclusion (SIE), is common in bacterial, human, and plant virus infections. We also report that HcPro’s induction of SIE is strain-specific and that this specificity is provided by the first four amino acid residues of the protein. Consistent with the mechanism of SIE, the study found that HcPro does not exclude a resident virus. Additionally, HcPro’s induction of SIE was observed to function independently of its ability to suppress antiviral RNA silencing. HcPro’s induction of SIE is relevant given the prevalence of multiple PVY strains that routinely co-infect the same cell and that may lead to recombination and emergence of new and more virulent strains. Furthermore, cross-protection or systemic acquired resistance (SAR) that is employed in plant virus disease management occurs when SIE moves from the cellular level and spreads systemically, emphasizing the importance of studying SIE. Full article

(This article belongs to the Special Issue Viral Infections and Viral Pathogenesis)

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14 pages, 1016 KB

Open AccessReview

Anti-Müllerian Hormone as a Biomarker for Predicting Testicular Sperm Extraction Outcomes in Azoospermic Patients: A Comprehensive Systematic Review and Meta-Analysis

by Dragoș Puia, Marius Ivănuță, Mihaela Corlade-Andrei, Ovidiu Daniel Bîcă, Bogdan Doroftei and Cătălin Pricop

Int. J. Mol. Sci. 2025, 26(23), 11643; https://doi.org/10.3390/ijms262311643 (registering DOI) - 1 Dec 2025

Male infertility represents a major clinical and societal issue, with azoospermia being one of its most severe forms. Anti-Müllerian Hormone (AMH) has been proposed as a potential biomarker for predicting testicular sperm extraction (TESE) outcomes in men with non-obstructive azoospermia (NOA). This study [...] Read more.

Male infertility represents a major clinical and societal issue, with azoospermia being one of its most severe forms. Anti-Müllerian Hormone (AMH) has been proposed as a potential biomarker for predicting testicular sperm extraction (TESE) outcomes in men with non-obstructive azoospermia (NOA). This study aimed to systematically evaluate the association between AMH levels and sperm retrieval success. We included studies on men with NOA reporting TESE outcomes by AMH level, excluding those without full text or with insufficient data. When cohorts overlapped, the most complete study was used, following PICO criteria focused on AMH measurements and sperm retrieval rates (SRR). A comprehensive search identified 133 potentially relevant publications. Of these, 11 studies published between 2006 and 2023, including 1280 patients, met the inclusion criteria. Pooled analyses were performed using random-effects models. This meta-analysis was recorded in the PROSPERO database (registration ID: CRD420251065256). Reported SRRs ranged from 30.35% to 76.27%. Meta-analysis of nine studies assessing serum AMH concentrations revealed significant heterogeneity (I² = 88%). Elevated serum AMH was negatively associated with SRR (standardized mean difference [SMD] = −2.58; 95% CI: −4.73 to −0.44; p < 0.00001). In contrast, seminal plasma AMH levels (two studies) showed no significant association with SRR (I² = 82%). Similarly, preoperative FSH levels (nine studies) did not demonstrate a consistent association with SRR, despite higher mean concentrations in patients with successful TESE (p = 0.02; SMD = −4.86; 95% CI: −9.07 to −0.66). Serum AMH levels are significantly associated with TESE outcomes in men with NOA. However, the predictive value of AMH and other hormonal markers is limited by high inter-individual variability and overlapping values between successful and unsuccessful cases. These findings underscore the complexity of NOA and highlight the need to interpret hormonal markers within a broader clinical and biochemical context. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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18 pages, 1475 KB

Open AccessReview

Immune-Guided Bone Healing: The Role of Osteoimmunity in Tissue Engineering Approaches

by Serena Munaò, Alessandra Armeli, Desirèe Bonfiglio, Antonella Iaconis and Giovanna Calabrese

Int. J. Mol. Sci. 2025, 26(23), 11642; https://doi.org/10.3390/ijms262311642 (registering DOI) - 1 Dec 2025

The skeletal and immune systems are intricately linked, forming a dynamic interface that regulates both bone homeostasis and immune function. This bidirectional relationship, central to the field of osteoimmunology, highlights how bone and immune cells interact via shared progenitors and signaling pathways. Osteoclasts [...] Read more.

The skeletal and immune systems are intricately linked, forming a dynamic interface that regulates both bone homeostasis and immune function. This bidirectional relationship, central to the field of osteoimmunology, highlights how bone and immune cells interact via shared progenitors and signaling pathways. Osteoclasts and osteoblasts not only coordinate bone remodeling but also influence hematopoietic and immune functions within the bone marrow microenvironment. The concept of the “bone immune system” underscores this crosstalk, particularly in pathological and regenerative contexts. Despite progress, contradictory findings complicate our understanding of cytokine activity. Pro-inflammatory mediators such as TNF-α and IL-17 are typically associated with bone loss, yet under certain conditions, they paradoxically promote repair by stimulating osteoblast differentiation. Conversely, anti-inflammatory cytokines like IL-10 and TGF-β are generally protective, but their effects vary depending on local context, sometimes even impairing regeneration. These inconsistencies highlight unresolved questions and gaps in mechanistic insight into immune–bone interactions. Bone tissue engineering (BTE) has advanced through biomimetic scaffolds, osteogenic cells, and bioactive molecules, offering hope for large defect repair. However, clinical translation remains limited, largely because immune modulation is not fully integrated into scaffold design. Current preclinical models often fail to capture the complexity of immune–skeletal interplay, reducing predictive value. Addressing these gaps requires improved models and systematic evaluation of immunoregulatory biomaterials, paving the way for more effective and personalized regenerative therapies. Full article

(This article belongs to the Section Molecular Immunology)

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15 pages, 2079 KB

Open AccessArticle

Liproxstatin-1 Protects SH-SY5Y Cells by Inhibiting H₂O₂-Induced Excessive Mitophagy and Apoptosis

by Tingting Yan, Feng Ding, Zhongyuan Fang and Yan Zhao

Int. J. Mol. Sci. 2025, 26(23), 11641; https://doi.org/10.3390/ijms262311641 (registering DOI) - 1 Dec 2025

Oxidative stress is a critical factor in the pathogenesis of various neuronal disorders, causing cellular damage and mitochondrial dysfunction. This study aimed to explore the protective effects of liproxstatin-1 against H₂O₂-induced neural oxidative damage and elucidate the underlying mechanisms. [...] Read more.

Oxidative stress is a critical factor in the pathogenesis of various neuronal disorders, causing cellular damage and mitochondrial dysfunction. This study aimed to explore the protective effects of liproxstatin-1 against H₂O₂-induced neural oxidative damage and elucidate the underlying mechanisms. Our findings demonstrated that 500 μmol/L H₂O₂ treatment induced mitochondrial dysfunction and apoptosis in SH-SY5Y cells, while 1 μmol/L liproxstatin-1 effectively mitigated these cytotoxic effects by restoring mitochondrial integrity and enhancing cell viability. Furthermore, 500 μmol/L H₂O₂ exposure significantly suppressed the activation of the protein kinase B/ mammalian target of rapamycin signaling pathway and triggered excessive mitophagy. Pretreatment with 1 μmol/L liproxstatin-1 attenuated the damage by H₂O₂, suggesting its protective role. Collectively, our results indicated that 500 μmol/L H₂O₂ induces cytotoxicity through oxidative damage, protein kinase B/ mammalian target of rapamycin pathway inhibition, and aberrant mitophagy, ultimately leading to apoptosis; meanwhile, 1 μmol/L liproxstatin-1 counteracted these effects by preserving mitochondrial function, suppressing excessive mitophagy, and inhibiting apoptotic pathways, thereby protecting SH-SY5Y cells from H₂O₂-induced cytotoxicity. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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1 pages, 137 KB

Open AccessCorrection

Correction: Salloum-Asfar et al. MicroRNA Profiling Identifies Age-Associated MicroRNAs and Potential Biomarkers for Early Diagnosis of Autism. Int. J. Mol. Sci. 2025, 26, 2044

by Salam Salloum-Asfar, Samia M. Ltaief, Rowaida Z. Taha, Wared Nour-Eldine, Sara A. Abdulla and Abeer R. Al-Shammari

Int. J. Mol. Sci. 2025, 26(23), 11640; https://doi.org/10.3390/ijms262311640 - 1 Dec 2025

The authors wish to make the following corrections to this paper [...] Full article

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

2 pages, 1096 KB

Open AccessCorrection

Correction: Zou et al. Transportin-3 Facilitates Uncoating of Influenza A Virus. Int. J. Mol. Sci. 2022, 23, 4128

by Jiahui Zou, Luyao Yu, Yinxing Zhu, Shuaike Yang, Jiachang Zhao, Yaxin Zhao, Meijun Jiang, Shengsong Xie, Hailong Liu, Changzhi Zhao and Hongbo Zhou

Int. J. Mol. Sci. 2025, 26(23), 11639; https://doi.org/10.3390/ijms262311639 (registering DOI) - 1 Dec 2025

Error in Figure [...] Full article

(This article belongs to the Section Molecular Biology)

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11 pages, 1318 KB

Open AccessArticle

Antibody-Dependent Cytotoxicity of Monocytes in Preeclampsia Is Associated with Soluble Forms of HLA

by Aleksey M. Krasnyi, Leya E. Sorokina, Anastacia Maria Argentova-Stevens, Diana N. Kokoeva, Aleksey A. Alekseev, Tatjana Jankevic, Natalia E. Kan, Victor L. Tyutyunnik and Gennady T. Sukhikh

Int. J. Mol. Sci. 2025, 26(23), 11638; https://doi.org/10.3390/ijms262311638 - 1 Dec 2025

Preeclampsia (PE) is a serious gestational complication that affects the lives of the mother and the child. Women with PE showed higher levels of pro-inflammatory cytokines secreted by leukocytes compared with women with normal pregnancies. The differences are most noticeable in the percentage [...] Read more.

Preeclampsia (PE) is a serious gestational complication that affects the lives of the mother and the child. Women with PE showed higher levels of pro-inflammatory cytokines secreted by leukocytes compared with women with normal pregnancies. The differences are most noticeable in the percentage of CD16+ monocytes, although the mechanism underlying this increase remains unclear. The CD16 receptor is critical for antibody-dependent cellular cytotoxicity, and by binding to antibodies on the surface of target cells, it activates their death. In this study, we examined the effect of soluble placental factors on the expression of CD16 monocytes and the potential role the soluble form of human leukocyte antigen (HLA) has on CD16 monocyte expression. At the first stage of our study, we collected samples of placental villi fragments from 58 pregnant women (38 women with PE and 20 with a healthy pregnancy). Then we studied the effect of placental villus-conditioned culture medium on CD16 expression by monocytes derived from the same women. It was shown that the content of CD16+ monocytes increased significantly in women with PE within 3 h and to a lesser extent in women with a healthy pregnancy (p = 0.009). Also, the addition of the recombinant histocompatibility HLA-B to the placental villus-conditioned culture medium blocks the induction of CD16 expression on monocytes. At the second stage of our study, we typed HLA class I and class II alleles in the umbilical cord blood samples and the venous blood samples taken from 38 women with PE and 40 women with a normal pregnancy. It was found that certain HLA class II alleles predominate in women with preeclampsia. The DRB1*01:01:01G allele showed the greatest difference (p < 0.001). Analyzing five alleles simultaneously makes it possible to predict the PE with AUC = 0.76. Evaluation of unique children’s alleles also showed that class II alleles have greater differences among them than class I alleles. The DQB1*06:03:01G allele had the greatest differences with p = 0.03 (the number was higher in the control group). Performing an analysis of four alleles of children simultaneously allowed us to predict PE with an AUC of 0.64. This work suggests that the activation of CD16+ monocyte expression occurs due to the interaction of soluble placental antigens with monocytes. The most likely way to activate CD16 expression on monocytes is by HLA class II (both maternal and fetal) interaction with CD4 receptors on the surface of monocytes, whereas HLA class I is capable of blocking this process. Evaluation of maternal HLA alleles may be a significant marker for predicting PE. Full article

(This article belongs to the Special Issue Pathogenesis of Preeclampsia: From a Molecular Perspective)

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37 pages, 1831 KB

Open AccessReview

Natural Products as Potential Therapeutic Candidates for Diabetic Kidney Disease: Molecular Mechanisms, Translational Challenges, and Future Prospects

by Manqi Guo, Lihua Ni and Xiaoyan Wu

Int. J. Mol. Sci. 2025, 26(23), 11637; https://doi.org/10.3390/ijms262311637 - 1 Dec 2025

Diabetic Kidney Disease (DKD) is one of the primary causes of chronic kidney disease. However, existing clinical interventions remain insufficiently effective in halting its progression, highlighting the need to explore novel therapeutic approaches. In recent years, natural products such as Abelmoschus manihot have [...] Read more.

Diabetic Kidney Disease (DKD) is one of the primary causes of chronic kidney disease. However, existing clinical interventions remain insufficiently effective in halting its progression, highlighting the need to explore novel therapeutic approaches. In recent years, natural products such as Abelmoschus manihot have shown growing potential in lowering urinary protein. Building on this background, this paper systematically summarizes preclinical evidence that certain natural substances ameliorate DKD by targeting key pathogenic mechanisms, including inflammation and oxidative stress. It also contrasts the pros and cons of natural medicines with existing therapies, while further investigating advanced pharmaceutical technologies for the translation of natural medicines into clinical applications. However, the clinical translation of natural medicines currently confronts multiple challenges, including small sample sizes, insufficient follow-up periods, individual heterogeneity, and insufficient accumulation of safety data. Therefore, future efforts should prioritize the in-depth exploitation of medicinal plant resources and their clinical translation, with a focus on enhancing high-quality translational clinical studies. This strategy seeks to provide novel insights and practical solutions for treating DKD. Full article

(This article belongs to the Collection Latest Review Papers in Bioactives and Nutraceuticals)

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2 pages, 249 KB

Open AccessCorrection

Correction: Skenderidou et al. Functional Food Ingredients Enhancing Immune Health: A Systematic Review. Int. J. Mol. Sci. 2025, 26, 8408

by Irene Skenderidou, Stefanos Leontopoulos and Prodromos Skenderidis

Int. J. Mol. Sci. 2025, 26(23), 11636; https://doi.org/10.3390/ijms262311636 - 1 Dec 2025

In the original publication [...] Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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14 pages, 1377 KB

Open AccessReview

HIV-1 and Its Strategy for Hiding Viral cDNA from STING-Mediated Innate Immunity

by Anna Mashkovskaia, Yulia Agapkina, Tatiana Oretskaya, Marina Gottikh and Andrey Anisenko

Int. J. Mol. Sci. 2025, 26(23), 11635; https://doi.org/10.3390/ijms262311635 - 1 Dec 2025

Human immunodeficiency virus type 1 (HIV-1) is known to activate cytosolic DNA sensor pathways, such as the cGAS-STING pathway, the activation of which leads to interferon production. The primary source of this activation is reverse transcription of the viral RNA genome into cDNA, [...] Read more.

Human immunodeficiency virus type 1 (HIV-1) is known to activate cytosolic DNA sensor pathways, such as the cGAS-STING pathway, the activation of which leads to interferon production. The primary source of this activation is reverse transcription of the viral RNA genome into cDNA, which occurs in the cytoplasm. However, the degree of cytosolic DNA sensor activation during HIV-1 infection is significantly lower compared to that induced by DNA-containing viruses or even by the related HIV-2. This can be attributed to the successful evasion of innate immune recognition pathways by HIV-1, particularly through the disruption of cGAS-STING signaling pathway activation. In this review, we summarize the available information regarding the mechanisms employed by HIV-1 to conceal viral cDNA from cytosolic DNA sensors. Deciphering these mechanisms may reveal potential vulnerabilities that could be targeted to develop novel antiviral approaches. Full article

(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection: 2nd Edition)

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2 pages, 166 KB

Open AccessCorrection

Correction: Serrasqueiro et al. Targeting the Mannose Receptor with Functionalized Fucoidan/Chitosan Nanoparticles Triggers the Classical Activation of Macrophages. Int. J. Mol. Sci. 2023, 24, 9908

by Filipa Serrasqueiro, Ana Isabel Barbosa, Sofia A. Costa Lima and Salette Reis

Int. J. Mol. Sci. 2025, 26(23), 11634; https://doi.org/10.3390/ijms262311634 - 1 Dec 2025

There was an error in the original publication [...] Full article

(This article belongs to the Section Macromolecules)

26 pages, 1154 KB

Open AccessReview

The Effect of Silver Nanoparticle Addition on the Antimicrobial Properties of Poly(methyl methacrylate) Used for Fabrication of Dental Appliances: A Systematic Review

by Kacper Galant, Maja Podziewska, Maciej Chęciński, Kamila Chęcińska, Natalia Turosz, Dariusz Chlubek, Tomasz Korcz and Maciej Sikora

Int. J. Mol. Sci. 2025, 26(23), 11633; https://doi.org/10.3390/ijms262311633 - 30 Nov 2025

Polymethyl methacrylate (PMMA) is widely used in modern dentistry, particularly in prosthodontics, orthodontics, and maxillofacial surgery. To improve the properties of PMMA, silver nanoparticles (AgNPs) are incorporated to enhance the antibacterial, antiviral, and antifungal effects of this material. This study aims to evaluate [...] Read more.

Polymethyl methacrylate (PMMA) is widely used in modern dentistry, particularly in prosthodontics, orthodontics, and maxillofacial surgery. To improve the properties of PMMA, silver nanoparticles (AgNPs) are incorporated to enhance the antibacterial, antiviral, and antifungal effects of this material. This study aims to evaluate the antimicrobial properties of AgNPs as an additive to PMMA. Medical databases covered by the ACM, BASE, PubMed, and Scopus engines were searched. Of the 670 identified records, 23 studies were included that assessed the antibacterial and antifungal properties gained by incorporating AgNPs into PMMA. All of the studies included also contained a control group—PMMA without additives. Studies that evaluated nanoparticles other than AgNPs or materials other than PMMA were excluded. The data collected from the articles included the size and concentration of the nanoparticles, the method of sample preparation, sample size, information on the effect of nanoparticles on antimicrobial properties, and the contact time between the sample and the test tube containing fungi or bacteria. The data were presented in tables and graphs. The analysis indicated that increasing the weight percent concentration of AgNPs or extending the incubation time increases the antifungal efficacy. The result of Tau Kendall correlation showed that the pairs of data, concentration/incubation time and outcomes, are inversely proportional for fungi (p < 0.01). The results of the study are not entirely conclusive. Some limitations suggest the need for more standardized studies, which ideally should be conducted on human research groups and followed by a study of these properties and their effects on the human body. This systematic review followed PRISMA 2020 guidelines. The protocol was submitted to the Open Science Framework Registries (1 December 2024). Full article

(This article belongs to the Special Issue Nanoparticles in Nanobiotechnology and Nanomedicine: 2nd Edition)

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28 pages, 1897 KB

Open AccessReview

From Synaptic Plasticity to Neurotoxicity: Endocannabinoid Influence on Addiction and Neurodegeneration

by Balapal S. Basavarajappa and Shivakumar Subbanna

Int. J. Mol. Sci. 2025, 26(23), 11632; https://doi.org/10.3390/ijms262311632 - 30 Nov 2025

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent [...] Read more.

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components—cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes—modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation—pathological features common to Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline. Full article

(This article belongs to the Special Issue From Synapse to Substance Use: Endocannabinoids and Cannabinoid Receptors in Brain Plasticity and Addiction Circuits)

20 pages, 1142 KB

Open AccessReview

Secretory Leukocyte Protease Inhibitor: A Pleiotropic Molecule for the Potential Diagnosis of and Therapy for Acute Kidney Injury

by Rui Chen, Shiyun Gu, Fenfen Xiong, Lili Ji, Zhi-Jun Zhang, Bin Yang and Yuanyuan Wu

Int. J. Mol. Sci. 2025, 26(23), 11631; https://doi.org/10.3390/ijms262311631 - 30 Nov 2025

Acute kidney injury (AKI) remains a common clinical syndrome associated with high morbidity and mortality. However, effective diagnostic biomarkers and specific therapeutic interventions are still lacking. Secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor with pleiotropic functions, has emerged as an early [...] Read more.

Acute kidney injury (AKI) remains a common clinical syndrome associated with high morbidity and mortality. However, effective diagnostic biomarkers and specific therapeutic interventions are still lacking. Secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor with pleiotropic functions, has emerged as an early diagnostic and prognostic biomarker for AKI. Clinical studies reveal significant elevation of serum SLPI in AKI patients compared to non-AKI patients at the acute phase following post-cardiovascular surgery, supporting its diagnostic potential. Furthermore, evidence also suggests that SLPI showed prognostic value for kidney transplantation and chronic kidney disease progression associated with diverse etiology, including diabetes. In addition, current evidence highlights the biological functions of SLPI in inhibiting NF-κB activities, suppressing neutrophil extracellular trap formation, modulating phagocytosis, regulating cell apoptosis, proliferation, differentiation, and potentially fibrosis across various disease contexts. Preclinical studies demonstrate that administration of recombinant SLPI ameliorates renal dysfunction in multiple AKI models, including ischemia–reperfusion injury and nephrotoxic models induced by gentamicin or cisplatin. Furthermore, the antifibrotic properties of SLPI underscore its therapeutic potential in halting AKI progression to chronic kidney disease. By integrating available evidence, this review aims to elucidate that, as an early acute-phase response molecule, SLPI serves dual roles as not only an early diagnostic and prognostic biomarker for AKI, but also a renoprotective molecule countering kidney injury. Full article

(This article belongs to the Special Issue Acute Kidney Injury: Molecular Mechanism and Targeted Therapeutic Approaches)

28 pages, 2476 KB

Open AccessArticle

Gene Polymorphisms Determining Sex Hormone-Binding Globulin Levels and Endometriosis Risk

by Tatiana Ponomareva, Oxana Altukhova, Maria Churnosova, Inna Aristova, Evgeny Reshetnikov, Mikhail Churnosov and Irina Ponomarenko

Int. J. Mol. Sci. 2025, 26(23), 11630; https://doi.org/10.3390/ijms262311630 - 30 Nov 2025

Endometriosis is a hormone-dependent disease, in the pathophysiology of which sex hormones (androgens, estrogens, etc.) are involved. The level of bioactive androgens/estrogens (in the free state) in the organism largely depends on sex hormone-binding globulin (SHBG), which binds/transports a significant portion of the [...] Read more.

Endometriosis is a hormone-dependent disease, in the pathophysiology of which sex hormones (androgens, estrogens, etc.) are involved. The level of bioactive androgens/estrogens (in the free state) in the organism largely depends on sex hormone-binding globulin (SHBG), which binds/transports a significant portion of the androgens/estrogens of the body and, due to this, changes the amount of these hormones in a free state (bioactive), which may be important in the development of endometriosis. The study was devoted to identifying the link between the genetic determinants (single nucleotide polymorphisms [SNPs]) of SHBG (according to predating genome-wide associative studies [GWAS]) and the risk of endometriosis in the Caucasian women of Russia. The study was accomplished on a total sample of 1368 women (395 endometriosis; 973 endometriosis free [controls]). Nine loci with an impact on SHBG level in predating GWAS have been examined. The search for associations of these loci with endometriosis was carried out: both their independent effects and interlocus interactions with an in silico interpretation of the functionality/pathways in which endometriosis-related loci and strongly linked SNPs were involved have been evaluated. Polymorphic locus rs440837 (A > G) ZBTB10 correlated with endometriosis development (recessive genetic model): the SHBG-raising genotype GG rs440837 (A > G) ZBTB10 serves as a risk factor for the disease formation; its presence in the genotype almost doubles the risk of endometriosis (OR = 1.91; 95%CI = 1.13–2.98; p_perm = 0.024; power = 81.13%). The SHBG-impacts of 7 SNPs from 9 analyzed loci such as rs17496332 (A > G) PRMT6, rs780093 (C > T) GCKR, rs10454142 (T > C) PPP1R21, rs3779195 (T > A) BAIAP2L1, rs440837 (A > G) ZBTB10, rs7910927 (G > T) JMJD1C, and rs8023580 (T > C) NR2F2 interacting with each other have been endometriosis-associated. Endometriosis-causal SNP rs440837 (A > G) ZBTB10 and 5 proxy SNPs determine the DNA interaction in the region of 3 genes (RP11-48B3.3, RP11-48B3.4, ZBTB10) with 22 transcription factors and, due to this, affect the processes of development of the endocrine system, gene transcription regulation, TGF-beta signaling pathway, regulation of cell proliferation/differentiation, etc. In conclusion, the results of this study showed the endometriosis risk effect of the SHBG-impact polymorphic variants. Full article

(This article belongs to the Special Issue Genes and Human Diseases: 3rd Edition)

19 pages, 2418 KB

Open AccessArticle

Integrative Discovery Through Network Pharmacology and Molecular Docking Approaches of Phenolic Compounds Isolated from Torreya nucifera to Treat Rheumatoid Arthritis

by Duc Dat Le, Thinhulinh Dang, Vinhquang Truong, Soojung Yu, Seung-Hwa Yang, Moon-Hee Choi and Mina Lee

Int. J. Mol. Sci. 2025, 26(23), 11629; https://doi.org/10.3390/ijms262311629 - 30 Nov 2025

Torreya nucifera, a consumable botanical species native to the southern regions of Korea, has a history of ethnopharmacological application to treat inflammatory conditions. This study employed feature-based molecular networking and integrated with the GNPS database to separate and identify ten phenolic compounds [...] Read more.

Torreya nucifera, a consumable botanical species native to the southern regions of Korea, has a history of ethnopharmacological application to treat inflammatory conditions. This study employed feature-based molecular networking and integrated with the GNPS database to separate and identify ten phenolic compounds from T. nucifera. We further investigated the therapeutic potential of these isolated compounds and their structural features in the context of rheumatoid arthritis. Protein–protein interaction networks, constructed using compound–target and disease-associated target data, identified NFKB1, RELA, and TNFRSF1A as key hub genes. Gene Ontology (GO) enrichment analysis revealed inflammatory response as the most significantly modulated biological process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the NF–kB signaling pathway is the most critical of the regulatory cascades influencing the pathogenesis of rheumatoid arthritis. Molecular docking studies verified strong binding affinities between the identified compounds and key target proteins. Furthermore, Western blot results validate that T. nucifera extract suppressed the LPS-activated NF–kB signaling pathways by inhibiting p65 and IκBα phosphorylation. The results underscore the significance of T. nucifera and its anti-inflammatory properties in relation to rheumatoid arthritis, establishing a scientific basis to formulate plant-based products within functional foods, nutraceuticals, and therapeutic interventions targeting rheumatoid arthritis. Full article

(This article belongs to the Special Issue Natural Product as Therapeutic Agent: From Molecular Targets to Cellular and Functional Modulation)

18 pages, 962 KB

Open AccessReview

CPX-351 and the Frontier of Nanoparticle-Based Therapeutics in Acute Myeloid Leukemia

by Ioannis Konstantinidis, Sophia Tsokkou, Antonios Keramas, Eleni Gavriilaki, Georgios Delis and Theodora Papamitsou

Int. J. Mol. Sci. 2025, 26(23), 11628; https://doi.org/10.3390/ijms262311628 - 30 Nov 2025

Acute myeloid leukemia (AML) continues to carry a dismal prognosis in older adults and those with secondary or high-risk disease, where conventional 7+3 chemotherapy has long delivered complete remission rates below 40% and median overall survival often under 6 months. CPX-351 (Vyxeos), a [...] Read more.

Acute myeloid leukemia (AML) continues to carry a dismal prognosis in older adults and those with secondary or high-risk disease, where conventional 7+3 chemotherapy has long delivered complete remission rates below 40% and median overall survival often under 6 months. CPX-351 (Vyxeos), a liposomal co-encapsulation of cytarabine and daunorubicin at a fixed synergistic 5:1 molar ratio, was designed to overcome the pharmacokinetic mismatch that undermines the traditional regimen. This review critically examines the preclinical rationale and clinical evidence for CPX-351, with particular attention to whether its nanoparticle platform truly represents a breakthrough or merely an incremental refinement of decades-old cytotoxics. Across phase I–III trials and real-world cohorts, CPX-351 consistently outperformed standard 7 + 3 in its approved populations of newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC) in patients aged 60–75 years. In the pivotal phase III study (n = 309), CPX-351 improved median overall survival from 5.95 to 9.56 months (HR 0.69, 95% CI 0.52–0.90; p = 0.005) and raised the complete remission rate from 33.3% to 47.7%, while facilitating allogeneic transplantation in 34% as opposed to 25% of patients. A five-year follow-up sustained the separation in survival curves, and post-hoc analyses of responders showed median overall survival exceeding 25 months with CPX-351 versus approximately 10 months with 7+3 (HR 0.49). Real-world series have reported composite remission rates of 53–60%, measurable residual disease negativity in up to 65% of responders, and median overall survival of 12–20 months, depending on transplant utilization. Despite these gains, the absolute survival benefit remains modest, prolonged cytopenias are universal, and outcomes in TP53-mutated or younger adverse-risk patients are still poor, raising legitimate questions about cost-effectiveness and generalizability. Nonetheless, CPX-351 stands as the first clinically validated example of ratiometric nanomedicine in oncology, proving that reformulating established drugs can yield meaningful progress where novel agents have often failed. Full article

(This article belongs to the Special Issue Nanoparticles in Molecular Pharmaceutics)

19 pages, 1159 KB

Open AccessArticle

Chemical Transformations of Lignin Under the Action of 1-Butyl-3-Methylimidazolium Ionic Liquids: Covalent Bonding and the Role of Anion

by Artyom V. Belesov, Ilya I. Pikovskoi, Anna V. Faleva and Dmitry S. Kosyakov

Int. J. Mol. Sci. 2025, 26(23), 11627; https://doi.org/10.3390/ijms262311627 - 30 Nov 2025

1-Butyl-3-methylimidazolium (bmim) ionic liquids (ILs) are widely used for lignocellulose fractionation, yet their role extends beyond mere solvents. This study revealed that bmim-based ILs act as active chemical reagents, modifying the lignin structure in an anion-dependent manner. Thermal treatment (80–150 °C) of spruce [...] Read more.

1-Butyl-3-methylimidazolium (bmim) ionic liquids (ILs) are widely used for lignocellulose fractionation, yet their role extends beyond mere solvents. This study revealed that bmim-based ILs act as active chemical reagents, modifying the lignin structure in an anion-dependent manner. Thermal treatment (80–150 °C) of spruce dioxane lignin with [bmim]OAc, [bmim]Cl, and [bmim]MeSO₄ resulted in two distinct transformation pathways. In [bmim]MeSO₄, acidic catalysis dominates, leading to lignin condensation (increase in weight-average molecular weight, M_w, to 15.2 kDa at 150 °C) and intense sulfur incorporation (up to 9.9%) via anion-derived methylation/sulfation. Conversely, [bmim]OAc promotes depolymerization (decrease in M_w to 3.6 kDa) and efficient covalent bonding of the bmim cation to lignin (up to 10.8 cations per 100 aromatic units and a 6.5% nitrogen content at 150 °C), preventing condensation. Two-dimensional NMR and HPLC-HRMS analyses revealed the formation of a C–C bond between the C₂ atom of the imidazole ring and the α-carbon of the phenylpropane lignin fragments and allowed for the identification of a number of individual nitrogen-containing lignin oligomers in the [bmim]OAc-treated samples. Their formation likely proceeds via nucleophilic addition of the N-heterocyclic carbene (NHC), derived from the bmim cation by deprotonation with the highly basic acetate anion, to aldehyde groups. The action of [bmim]Cl primarily induces acid-catalyzed transformations of lignin with minimal covalent modification. These findings redefine imidazolium ILs as reactive media in biorefining, where their covalent interactions can influence the properties of lignin but complicate its native structure and the recyclability of the IL. Full article

(This article belongs to the Collection State-of-the-Art Macromolecules in Russia)

20 pages, 663 KB

Open AccessReview

Cancer-Associated Cachexia in the Era of Obesity

by Joyce Cristina Ferreira de Resende, Márcia Fábia Andrade, Fabiana Amaral Ferreira, José Pinhata Otoch, Lívia Clemente Motta-Teixeira and Marilia Seelaender

Int. J. Mol. Sci. 2025, 26(23), 11626; https://doi.org/10.3390/ijms262311626 - 30 Nov 2025

Obesity and cancer cachexia represent opposite ends of the body mass index (BMI) spectrum. However, despite this apparent dichotomy, both conditions share critical metabolic alterations, primarily driven by inflammation, metabolic alterations and changes in adipose tissue biology. Obesity is characterised by chronic low-grade [...] Read more.

Obesity and cancer cachexia represent opposite ends of the body mass index (BMI) spectrum. However, despite this apparent dichotomy, both conditions share critical metabolic alterations, primarily driven by inflammation, metabolic alterations and changes in adipose tissue biology. Obesity is characterised by chronic low-grade inflammation and increased fat storage, while cancer cachexia involves severe weight loss, muscle atrophy, and lipolysis, with inflammation playing a central role in both conditions. Inflammatory cytokines such as TNF-α and IL-6 are increased in both scenarios, contributing to metabolic dysregulation and systemic energy imbalance. This review explores the shared inflammatory and metabolic pathways underlying obesity and cancer cachexia, with particular regard to the role of white adipose tissue (WAT). Moreover, we intend to highlight the importance of understanding the common mechanisms for the development of more effective therapeutic strategies for managing these complex metabolic disorders. Full article

(This article belongs to the Special Issue Advanced Research on Obesity and Cancer)

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