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Biomolecules

Biomolecules is a peer-reviewed, open access journal on structures and functions of bioactive and biogenic substances, molecular mechanisms with biological and medical implications as well as biomaterials and their applications. Biomolecules is published monthly online by MDPI.

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, MEDLINE, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Biochemistry and Molecular Biology) / CiteScore - Q1 (Biochemistry)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 19.4 days after submission; acceptance to publication is undertaken in 2.9 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.
Sections: published in 15 topical sections.
Testimonials: See what our editors and authors say about Biomolecules.
Companion journal: Receptors.

Impact Factor: 4.8 (2024); 5-Year Impact Factor: 5.6 (2024)

Imprint Information Journal Flyer Open Access ISSN: 2218-273X

Latest Articles

22 pages, 13763 KB

Open AccessArticle

Comprehensive Identification and Abscisic Acid-Responsive Expression Profiling of NAC Transcription Factor in Triterpenoid Saponin in Hedera helix

by Xiaoji Deng, Feixiong Zheng, Zhangting Xu, Xiaoping Mao, Zhenming Yu and Xiaoxia Shen

Biomolecules 2025, 15(11), 1557; https://doi.org/10.3390/biom15111557 (registering DOI) - 6 Nov 2025

Triterpenoid saponins are important secondary metabolites in plants. Abscisic acid (ABA), as one of the indispensable regulatory hormones in plants, promotes the accumulation of bioactive components in various plants, including triterpenoid saponins; however, its induced mechanism in Hedera helix remains unclear. In this [...] Read more.

Triterpenoid saponins are important secondary metabolites in plants. Abscisic acid (ABA), as one of the indispensable regulatory hormones in plants, promotes the accumulation of bioactive components in various plants, including triterpenoid saponins; however, its induced mechanism in Hedera helix remains unclear. In this study, the treatment of H. helix leaves with 100 μM ABA led to the identification of 7108 differentially expressed genes (DEGs) within 6 h post-treatment through transcriptomic and bioinformatic analysis. Enrichment analyses of GO terms and KEGG pathways indicated significant enrichment of DEGs in terpenoid backbone biosynthesis pathways. Analysis of DEGs revealed the NAC transcription factor, which is crucial for plant growth regulation, stress response, and secondary metabolite biosynthesis. A total of 182 HhNACs were identified at the genome-wide level, named HhNAC1 to HhNAC182 according to their chromosomal positions. Numerous ABA-responsive cis-regulatory elements (CREs) were presented at upstream promoters of HhNAC1 to HhNAC182. They demonstrated diversified tissue-specific expression profiling among stems, roots, and leaves of H. helix. Notably, HhNAC93 was predominantly expressed in H. helix leaves. Correlation analysis unveiled a markedly positive relationship among ABA-induced HhNAC93 expression, triterpenoid saponin accumulation, and the expression of essential saponin biosynthetic genes. HhNAC93 likely functions as a candidate regulator in triterpenoid saponin biosynthesis. These findings provide crucial evidence for further exploring the biological role of HhNAC transcription factor in H. helix. Full article

(This article belongs to the Special Issue From Gene to Metabolite: Decoding the Transcriptional Regulatory Networks Controlling the Biosynthesis of Bioactive Compounds)

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23 pages, 1933 KB

Open AccessReview

Re-Examination of Inflammation in Major Depressive Disorder: Bridging Systemic and Neuroinflammatory Insights

by Xinyu Ye, Yuen-Shan Ho and Raymond Chuen-Chung Chang

Biomolecules 2025, 15(11), 1556; https://doi.org/10.3390/biom15111556 - 5 Nov 2025

Major depressive disorder (MDD) is a multifaceted psychiatric disorder that has been a longstanding focus of research. However, its underlying mechanisms remain underexplored. Recently, the inflammatory hypothesis has gained attention, highlighting inflammation’s role in MDD progression. Potential contributors to increased systemic inflammation in [...] Read more.

Major depressive disorder (MDD) is a multifaceted psychiatric disorder that has been a longstanding focus of research. However, its underlying mechanisms remain underexplored. Recently, the inflammatory hypothesis has gained attention, highlighting inflammation’s role in MDD progression. Potential contributors to increased systemic inflammation in MDD include hyperactivation of the hypothalamic–pituitary–adrenal axis, dysregulation of the sympathetic nervous system, gut microbiota imbalances, the “pathogen host defense” hypothesis, and damage-associated molecular patterns. Traditional pathways explaining how systemic inflammation affects the central nervous system (CNS) do not fully account for the observed desynchrony between systemic and neuroinflammation in most depressed individuals. Alternative models suggest mechanisms such as reduced blood–brain barrier permeability and the involvement of immune cells from the skull. This review examines the link between inflammation and MDD, focusing on systemic and neuroinflammation interactions, with special emphasis on the heterogeneity of MDD symptoms and the potential impact of dysfunction in the brain’s lymphatic system. Gaining insight into the origins of inflammation in both the central nervous system and the peripheral body, along with their interactions, offers an important understanding of the inflammatory mechanisms associated with MDD for future treatment. Full article

(This article belongs to the Special Issue Impact of Systemic Inflammation on Neuroinflammation, Neurodegenerative Diseases and Mental Disorders)

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28 pages, 7307 KB

Open AccessArticle

Multi-Omics Reveals Active Components and Mechanisms of Heat-Processed Gypenosides Hepatoprotective Against APAP Injury

by Peng Xie, Qiuru Li, Shu Jiang, Miao Sun, Yu Duan, Changping Hu and Xianglan Piao

Biomolecules 2025, 15(11), 1555; https://doi.org/10.3390/biom15111555 - 5 Nov 2025

This study elucidates the hepatoprotective mechanisms of heat-processed Gynostemma pentaphyllum (Thunb.) Makino saponins (HGyp) against APAP-induced liver injury using serum pharmacochemistry, metabolomics, and network pharmacology. HGyp significantly mitigated liver damage in mice, as confirmed by biochemical and histopathological analyses. UPLC-MS identified 38 bioactive [...] Read more.

This study elucidates the hepatoprotective mechanisms of heat-processed Gynostemma pentaphyllum (Thunb.) Makino saponins (HGyp) against APAP-induced liver injury using serum pharmacochemistry, metabolomics, and network pharmacology. HGyp significantly mitigated liver damage in mice, as confirmed by biochemical and histopathological analyses. UPLC-MS identified 38 bioactive compounds, including 16 prototype saponins and 11 metabolites. Network pharmacology and molecular docking revealed damulin A/B, gypenosides (L/LI/LVI/XLVI), and ginsenosides (Rg3/Rd) as key components targeting GRB2, FGF2, MMP2, STAT3, CASP3, and HSP90A. Western blotting confirmed the HGyp-mediated downregulation of hepatic HSP90A and STAT3. Metabolomics identified four critical pathways, PPAR, ferroptosis, and the inflammatory mediator regulation of TRP channels involved in hepatoprotection. HGyp exerts multi-target effects via anti-inflammatory activity, apoptosis, and metabolism, providing a framework for Chinese medicine and ethnomedicine research. Full article

(This article belongs to the Topic Natural Products and Drug Discovery—2nd Edition)

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24 pages, 1843 KB

Open AccessReview

From Correlation to Causation: Defining Gene and RNA Function in Poultry Muscle Biology Using In Vivo Genetic Tools

by Bahareldin Ali Abdalla Gibril, Xuewen Chai and Jiguo Xu

Biomolecules 2025, 15(11), 1554; https://doi.org/10.3390/biom15111554 - 5 Nov 2025

A central challenge in functional genomics is understanding the difference between correlative transcriptomic observations and definitive causal understanding of gene function in vivo. Poultry skeletal muscle, a system of significant agricultural and biological importance, demonstrates this challenge. While transcriptomic studies have cataloged extensive [...] Read more.

A central challenge in functional genomics is understanding the difference between correlative transcriptomic observations and definitive causal understanding of gene function in vivo. Poultry skeletal muscle, a system of significant agricultural and biological importance, demonstrates this challenge. While transcriptomic studies have cataloged extensive RNA expression dynamics during muscle development and in growth-related myopathies like wooden breast, establishing causative roles for these molecules is lacking. This review synthesizes how advanced genetic tools are now enabling a shift from correlation to causation in avian muscle biology. We detail how viral vectors (e.g., adenovirus, lentivirus, and RCAS) and CRISPR/Cas9 systems have provided direct in vivo validation of the functional roles of specific mRNAs, miRNAs, lncRNAs, and circRNAs in regulating myogenesis, hypertrophy, and atrophy. We contrast this success in fundamental biology with the study of myopathies, which remains largely descriptive. Here, a wealth of transcriptomic data has identified dysregulated pathways, including ECM remodeling, metabolism, and inflammation, but functional validation for most candidates is absent. We argue that the critical next step is to apply this established functional genomics toolkit to disease models. By defining causal mechanisms, this research will not only address a major agricultural issue but also provide a model for using genetic tools to dissect complex traits in a post-genomic era. Full article

(This article belongs to the Section Molecular Biology)

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25 pages, 4122 KB

Open AccessArticle

Small Molecule Inhibitors of Nicotinamide N-Methyltransferase Enzyme for the Treatment of Osteosarcoma and Merkel Cell Carcinoma: Potential for the Development of a Targeted Therapeutic Strategy

by Veronica Pompei, Monia Cecati, Emma Nicol Serritelli, Eleonora Gerini, Roberto Campagna, Valentina Pozzi, Matthijs J. Van Haren, Nathaniel I. Martin, Monica Emanuelli and Davide Sartini

Biomolecules 2025, 15(11), 1553; https://doi.org/10.3390/biom15111553 - 5 Nov 2025

Nicotinamide N-methyltransferase (NNMT) enzyme catalyzes the N-methylation of nicotinamide and its overexpression has been reported in many neoplasms, favoring traits featuring an aggressive tumor cell phenotype. Our recent data demonstrated that NNMT upregulation in osteosarcoma (OS) and Merkel cell carcinoma (MCC) led to [...] Read more.

Nicotinamide N-methyltransferase (NNMT) enzyme catalyzes the N-methylation of nicotinamide and its overexpression has been reported in many neoplasms, favoring traits featuring an aggressive tumor cell phenotype. Our recent data demonstrated that NNMT upregulation in osteosarcoma (OS) and Merkel cell carcinoma (MCC) led to a significant increase in cell proliferation and migration ability, together with a reduction in sensitivity to chemotherapeutic treatment. Based on these findings, we investigated the impact of small molecule NNMT inhibitors 5-amino-1-methyl quinolinium (5-AMQ), 6-methoxynicotinamide (6MeONa) and Eli Lilly’s pyrimidine 5-carboxamide (EL-1) on U-2 OS and Saos-2 OS cell lines and MCC13 and MCC26 MCC cell lines. Following incubation of the cells with these compounds, cell viability, reactive oxygen species (ROS) production and apoptosis induction were evaluated. Cells were then subjected to combined treatment with inhibitors and cisplatin (CDDP), and viability and ROS levels were further analyzed. Our results clearly illustrate that cells treated with NNMT inhibitors underwent significant reductions in viability, increased ROS production and activation of apoptotic pathways. Given the association of NNMT with cancer aggressiveness, inhibiting its catalytic activity might present a novel strategy for counteracting cancer growth and chemoresistance, providing the rationale for an effective anti-cancer therapy based on the use of specific NNMT inhibitors. Full article

(This article belongs to the Special Issue Synthesis, Characterization and Validation of Small Molecule Compounds)

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29 pages, 2146 KB

Open AccessReview

Intestinal Mucin Glycosylation: Structural Regulation, Homeostasis Maintenance and Disease Association

by Yunye Li, Jia Pan, Huimin Liu and Chuanguo Liu

Biomolecules 2025, 15(11), 1552; https://doi.org/10.3390/biom15111552 - 5 Nov 2025

The intestinal barrier is a complex configuration that defends against external assaults and maintains intestinal health. Disruption of barrier function can lead to intestinal inflammation and various diseases. Mucins are the primary structural components of the intestinal barrier, and their extensive glycosylation is [...] Read more.

The intestinal barrier is a complex configuration that defends against external assaults and maintains intestinal health. Disruption of barrier function can lead to intestinal inflammation and various diseases. Mucins are the primary structural components of the intestinal barrier, and their extensive glycosylation is critical for their protective function. Mucin glycans enhance the physicochemical integrity of the mucus barrier, protect against enzymatic degradation, modulate host immune responses, and shape the gut microbiota by providing adhesion sites and selective nutrient sources. While proper glycosylation maintains barrier integrity, supports a balanced microbial ecosystem, and limits unnecessary immune activation, its disruption leads to compromised barrier function, microbial dysbiosis, increased intestinal permeability, and ultimately contributes to the development of chronic colitis and colorectal cancer. Therefore, mucin glycosylation plays a crucial role in preserving intestinal barrier integrity and preventing colonic diseases. This review summarizes the classifications and structural features of intestinal mucin glycosylation, elucidates their roles in maintaining barrier function and their pathological alterations in intestinal disorders, and highlights the implications of mucin glycosylation for precision diagnosis and targeted therapy of intestinal diseases. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 6662 KB

Open AccessArticle

Stigmasterol Protects Against Dexamethasone-Induced Muscle Atrophy by Modulating the FoxO3–MuRF1/MAFbx Signaling Pathway in C2C12 Myotubes and Mouse Skeletal Muscle

by Young-Sool Hah, Seung-Jun Lee, Yeung-Ho Ji, Jeongyun Hwang, Han-Gil Kim, Young-Tae Ju, Jun-Il Yoo and Seung-Jin Kwag

Biomolecules 2025, 15(11), 1551; https://doi.org/10.3390/biom15111551 - 5 Nov 2025

Glucocorticoid therapy, using agents like dexamethasone (Dexa), often leads to muscle atrophy by increasing protein degradation via the ubiquitin–proteasome system while suppressing protein synthesis. Stigmasterol, a phytosterol with known bioactivities, has an unexplored role in muscle atrophy. This study investigated stigmasterol’s protective effects [...] Read more.

Glucocorticoid therapy, using agents like dexamethasone (Dexa), often leads to muscle atrophy by increasing protein degradation via the ubiquitin–proteasome system while suppressing protein synthesis. Stigmasterol, a phytosterol with known bioactivities, has an unexplored role in muscle atrophy. This study investigated stigmasterol’s protective effects against Dexa-induced muscle atrophy and its impact on the FoxO3 and mTORC1 signaling pathways. Differentiated C2C12 myotubes were treated with Dexa (50 µM) ± stigmasterol (10 µM), and the morphology, viability, and protein levels in the FoxO3/MuRF1/MAFbx catabolic and mTOR/p70S6K/4E-BP1 anabolic signaling pathways were assessed. C57BL/6 mice received Dexa (20 mg/kg/day i.p.) ± stigmasterol (3 mg/kg/day oral) for 21 days, and the body/muscle mass, bone mineral density (BMD), fiber cross-sectional area (CSA), and muscle protein expression were measured. Stigmasterol (10 µM) was non-toxic and attenuated Dexa-induced reductions in myotube diameter and fusion in vitro, concurrent with suppressing Dexa-induced upregulation of FoxO3/MuRF1/MAFbx proteins and preventing the Dexa-induced dephosphorylation of mTOR/p70S6K/4E-BP1 proteins. In vivo, stigmasterol mitigated Dexa-induced losses in body weight, muscle mass, BMD, and fiber CSA. This protection was associated with attenuated upregulation of FoxO3 and MAFbx proteins in muscle tissue. Stigmasterol protected against Dexa-induced muscle atrophy in vitro and in vivo via modulation of the FoxO3–MAFbx catabolic pathway. These findings suggest stigmasterol inhibits excessive glucocorticoid-induced muscle protein breakdown. It therefore warrants further investigation as a potential therapeutic agent for glucocorticoid myopathy. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 3319 KB

Open AccessArticle

High-Intensity Pulse Magnetic Fields Affect Redox Homeostasis and Survival Rate of Escherichia coli According to Initial Level of Intracellular Glucose

by Pengbo Wang, Limeng Du, Yunchong Li, Zitang Xu, Luona Ye, Shuhan Dai, Li Xu, Jinyong Yan, Xiaoman Xie, Quanliang Cao, Min Yang, Xiaotao Han and Yunjun Yan

Biomolecules 2025, 15(11), 1550; https://doi.org/10.3390/biom15111550 - 5 Nov 2025

The biological effects of magnetic fields (MFs) have been studied and applied in medicine over the past four decades. However, the influence of high-intensity pulse magnetic fields (HI-PMFs), theorized to exert even stronger biological effects, is rarely reported. Herein, a study was conducted [...] Read more.

The biological effects of magnetic fields (MFs) have been studied and applied in medicine over the past four decades. However, the influence of high-intensity pulse magnetic fields (HI-PMFs), theorized to exert even stronger biological effects, is rarely reported. Herein, a study was conducted to investigate the biological effects of 2.5 T HI-PMF on the model organism Escherichia coli and its corresponding physiological alterations. After being treated by HI-PMF, a notable increase was observed in its intracellular NADH/NAD⁺ ratio, coupled with an improved cell survival rate. Transcriptome analysis revealed significant upregulation of genes related to glucose metabolism. Subsequent experiments confirmed that if the initial intracellular glucose level was relatively high and markedly decreased after being treated with HI-PMF, the cell density would significantly rise, owing to the alleviated inhibition of cell division. On the contrary, a lower initial intracellular glucose level led to cell death under HI-PMF. Furthermore, reactive oxygen species (ROS) production was proved to be the main cause attributed to the above phenomena. Therefore, our study suggests that HI-PMF treatment promotes ROS production, enhances cellular glucose metabolism, and consequently influences cell division and survival rate according to the initial level of intracellular glucose. Full article

(This article belongs to the Special Issue Industrial Microorganisms and Enzyme Technologies)

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13 pages, 31335 KB

Open AccessArticle

Bullous Pemphigoid Develops Independently of DAP12

by Manuela Pigors, Sabrina Patzelt, Maëlys Brudey, Shirin Emtenani, Stanislav Khil’chenko, Mayumi Kamaguchi, Niklas Reichhelm, Melissa Parker, Katja Bieber, Ralf J. Ludwig and Enno Schmidt

Biomolecules 2025, 15(11), 1549; https://doi.org/10.3390/biom15111549 - 5 Nov 2025

The adaptor molecule DNAX-activating protein of 12 kDa (DAP12) is broadly expressed in innate immune cells, but its role in autoimmunity remains unclear due to its dual regulatory functions. We investigated the contribution of the DAP12 pathway to bullous pemphigoid (BP), the most [...] Read more.

The adaptor molecule DNAX-activating protein of 12 kDa (DAP12) is broadly expressed in innate immune cells, but its role in autoimmunity remains unclear due to its dual regulatory functions. We investigated the contribution of the DAP12 pathway to bullous pemphigoid (BP), the most common autoimmune blistering disease, using a mouse model induced by transfer of anti-type XVII collagen (Col17) IgG. Repeated anti-Col17 IgG injections over 12 days produced comparable disease activity in DAP12-deficient and wildtype mice (n = 17/group), indicating that disease induction occurs independently of DAP12 signaling. Flow cytometry and immunofluorescence analysis of lesional skin further revealed a strong upregulation of the DAP12-associated triggering receptors expressed on myeloid cells (TREM) 1 in wildtype BP lesions, whereas TREM2⁺ cell frequencies in anti-Col17 IgG-treated wildtype and DAP12 knock-out animals were significantly lower than in healthy controls. Additional flow cytometry analysis demonstrated altered inflammatory infiltrates with notably reduced frequencies of Siglec-f⁺ eosinophils in DAP12-deficient vs. wildtype lesional skin. In addition, pharmacological inhibition of PI3Kδ, a downstream kinase of the DAP12/TREM pathway, did not affect disease progression in anti-Col17 IgG-induced BP. Collectively, these findings indicate that while DAP12 signaling modulates local immune cell composition, the DAP12/TREM1/2-axis does not influence overall disease activity in experimental BP. Full article

(This article belongs to the Special Issue Molecular Insights into Treatment and Prognosis of Autoimmune Bullous Diseases)

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19 pages, 1123 KB

Open AccessReview

Extracellular Vesicles in Calcific Aortic Valve Disease: From Biomarkers to Drug Delivery Applications

by Alberto Cook-Calvete, Maria Delgado-Marin, Blanca Fernandez-Rodriguez, Carlos Zaragoza and Marta Saura

Biomolecules 2025, 15(11), 1548; https://doi.org/10.3390/biom15111548 - 4 Nov 2025

Calcific aortic valve disease (CAVD) is a progressive disorder where molecular alterations occur long before visible calcification, making early biomarkers essential. Extracellular vesicles (EVs) have gained attention as stable biomarkers due to their lipid bilayer, which protects proteins, lipids, and RNAs, ensuring reliable [...] Read more.

Calcific aortic valve disease (CAVD) is a progressive disorder where molecular alterations occur long before visible calcification, making early biomarkers essential. Extracellular vesicles (EVs) have gained attention as stable biomarkers due to their lipid bilayer, which protects proteins, lipids, and RNAs, ensuring reliable detection even in archived samples. This review highlights the role of EVs as biomarkers and delivery tools in CAVD. EVs derived from valvular endothelial, interstitial, and immune cells carry disease-specific signatures, including osteogenic proteins (BMP-2, Annexins), inflammatory miRNAs (miR-30b, miR-122-5p), and lipid mediators. These reflect early pathogenic processes before macroscopic calcification develops. Their presence in minimally invasive samples such as blood, urine, or saliva facilitates diagnosis, while their stability supports long-term monitoring of disease progression and therapeutic response. Advances in purification and single-EV analysis increase specificity, though challenges remain in standardizing methods and distinguishing CAVD-derived EVs from those in atherosclerosis. Beyond diagnostics, engineered EVs show promise as therapeutic carriers. Delivery of anti-calcific miRNAs or combined RNA cargos has reduced calcification and inflammation in preclinical models. Overall, EVs act as molecular mirrors of CAVD, enabling early diagnosis, risk stratification, and novel therapeutic strategies. Yet, clinical translation requires technical refinement and validation of the disease-specific signatures. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aortic Diseases)

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14 pages, 5937 KB

Open AccessArticle

Kmt2c/Mll3 Haploinsufficiency Causes Autism-like Behavioral Deficits in Mice

by Kaijie Ma, Maria Webb, Haniya Hayder and Luye Qin

Biomolecules 2025, 15(11), 1547; https://doi.org/10.3390/biom15111547 - 4 Nov 2025

KMT2C (histone lysine N-methyltransferase 2C, also known as MML3, myeloid/lymphoid or mixed-lineage leukemia 3) is a causal gene for Kleefstra syndrome 2, a rare neurodevelopmental disorder. Recent human genetic studies have identified it as a high-risk gene for autism spectrum disorder (ASD), [...] Read more.

KMT2C (histone lysine N-methyltransferase 2C, also known as MML3, myeloid/lymphoid or mixed-lineage leukemia 3) is a causal gene for Kleefstra syndrome 2, a rare neurodevelopmental disorder. Recent human genetic studies have identified it as a high-risk gene for autism spectrum disorder (ASD), with 79% of patients harboring KMT2C variants having ASD. However, the causal link between KMT2C haploinsufficiency and ASD remains unclear. KMT2C/MLL3 encodes a histone methyltransferase, a core protein of the KMT2C/D COMPASS (complex proteins associated with Set1) complex, which plays fundamental roles in chromatin modification, occupancy, and gene expression. The expression of KMT2C/Kmt2c peaks during the developmental period in the human/mouse brain, which indicates the critical roles of KMT2C/Kmt2c in neurodevelopment. Here, we investigated the impact of germline Kmt2c haploinsufficiency on autism-like behavioral deficits in mice, which modeled humans carrying diverse KMT2C variants. Compared with Kmt2c^+/+ controls, Kmt2c haploinsufficiency mice had normal motor function without anxiety-like behaviors. Notably, Kmt2c haploinsufficiency mice exhibited autism-like social deficits and increased self-grooming in both males and females, which recapitulated the core phenotypes of ASD patients. Novel object recognition and spatial memory deficits were observed in male and female Kmt2c haploinsufficiency mice. This study reveals a causal link between Kmt2c haploinsufficiency and ASD-like behavioral deficits. These germline Kmt2c haploinsufficiency mice can be used for further studying the molecular mechanisms and developing therapeutic interventions for KMT2C haploinsufficiency-associated behavioral deficits. Full article

(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)

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26 pages, 3160 KB

Open AccessReview

Gut Microbiota and Ferroptosis in Colorectal Cancer: A Comprehensive Review of Mechanisms and Therapeutic Strategies to Overcome Immune Checkpoint Resistance

by Yingchang Cai, Feng Zhao and Xiaofei Cheng

Biomolecules 2025, 15(11), 1546; https://doi.org/10.3390/biom15111546 - 3 Nov 2025

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have achieved striking clinical efficacy in the subset of CRCs with mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), the vast majority of patients—those with proficient mismatch repair/microsatellite-stable (pMMR/MSS) [...] Read more.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have achieved striking clinical efficacy in the subset of CRCs with mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), the vast majority of patients—those with proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors—derive little benefit from current immunotherapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal accumulation of lipid peroxides, has emerged as a promising antitumor mechanism that can interact with and modulate antitumor immunity. Concurrently, the gut microbiota exerts powerful control over host metabolism and immune tone through microbial community structure and metabolite production; accumulating evidence indicates that microbiota-derived factors can either sensitize tumors to ferroptosis (for example, via short-chain fatty acids) or confer resistance (for example, indole-3-acrylic acid produced by Peptostreptococcus anaerobius acting through the AHR→ALDH1A3→FSP1/CoQ axis). In this review we synthesize mechanistic data linking microbial ecology, iron and lipid metabolism, and immune regulation to ferroptotic vulnerability in CRC. We discuss translational strategies to exploit this “microbiota–ferroptosis” axis—including precision microbiome modulation, dietary interventions, pharmacologic ferroptosis inducers, and tumor-targeted delivery systems—and we outline biomarker frameworks and trial designs to evaluate combinations with ICIs. We also highlight major challenges, such as interindividual microbiome variability, potential collateral harm to ferroptosis-sensitive immune cells, adaptive antioxidant compensation (e.g., NRF2/FSP1 activation), and safety/regulatory issues for live biotherapeutics. In summary, this review highlights that targeting the microbiota-ferroptosis axis may represent a rational and potentially transformative approach to reprogramming the tumor microenvironment and overcoming immune checkpoint resistance in pMMR/MSS colorectal cancer; however, further research is essential to validate this concept and address existing challenges. Full article

(This article belongs to the Special Issue Colorectal and Gastric Cancers: Molecular Mechanisms and Potential Biomarkers)

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13 pages, 2984 KB

Open AccessArticle

Expression Patterns of Interferons and Proinflammatory Cytokines in the Upper Respiratory Tract of Patients Infected by Different Viral Pathogens: Correlation with Age and Viral Load

by Roberto Ferrarese, Federica Novazzi, Gabriele Arcari, Angelo Genoni, Francesca Drago Ferrante, Nicola Clementi, Serena Messali, Antonino Maria Guglielmo Pitrolo, Francesca Caccuri, Antonio Piralla, Arnaldo Caruso, Fausto Baldanti and Nicasio Mancini

Biomolecules 2025, 15(11), 1545; https://doi.org/10.3390/biom15111545 - 3 Nov 2025

Respiratory tract infections are a major cause of morbidity and mortality. After the SARS-CoV-2 pandemic, pathogenetic mechanisms leading to more severe outcomes were investigated, including uncontrolled viral replication in the upper airways. This was only partially investigated for other respiratory viruses. We measured [...] Read more.

Respiratory tract infections are a major cause of morbidity and mortality. After the SARS-CoV-2 pandemic, pathogenetic mechanisms leading to more severe outcomes were investigated, including uncontrolled viral replication in the upper airways. This was only partially investigated for other respiratory viruses. We measured mucosal expression of IFN-β1, IFN-λ1, IFN-λ2/3, IL-1β, and IL-6 in patients infected by human metapneumovirus, human rhinovirus, human respiratory syncytial virus or type A influenza virus. A total of 806 nasopharyngeal swabs were collected from patients presenting at emergency departments or hospitalized. Viral load was inferred through cycle threshold determination, whereas cytokine levels were measured through mRNA detection. Each expression pattern was correlated with age, viral load, and specific infecting virus. IFN-β1 and IFN-λ2/3 showed a negative correlation with viral load, while IFN-λ1 and IL-6 exhibited the opposite trend, suggesting increased inflammation with higher viral load. This was more evident in the ≥70-year-old group, with significantly higher IL-6 levels. Higher viral load of potentially more pathogenic viruses was associated with higher IL-6 expression. Cytokine production in the upper respiratory tract is only partially influenced by age per se, with a more relevant role played by viral load and specific infecting virus. In older patients, this response is less coordinated and prone to elicit a proinflammatory response, especially when clinically impacting viruses are involved. Full article

(This article belongs to the Special Issue Dysregulated Cytokine Signals in Human Disease)

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19 pages, 777 KB

Open AccessReview

The Impact of Glycaemic Variability on Vascular Dysfunction in Diabetes

by Laura J. Offler, Liz K. Wells and Timothy M. Palmer

Biomolecules 2025, 15(11), 1544; https://doi.org/10.3390/biom15111544 - 3 Nov 2025

It is well established that vascular dysfunction is common in people with diabetes mellitus and is associated with increased risk of heart attack, ischaemic stroke and peripheral vascular disease. Although our understanding of the molecular mechanisms responsible is incomplete, persistent hyperglycaemia observed in [...] Read more.

It is well established that vascular dysfunction is common in people with diabetes mellitus and is associated with increased risk of heart attack, ischaemic stroke and peripheral vascular disease. Although our understanding of the molecular mechanisms responsible is incomplete, persistent hyperglycaemia observed in poorly controlled diabetes has long been thought to be a critical factor. Multiple studies have, therefore, investigated the effects of poor glycaemic control on vascular function in multiple experimental settings, from in vitro and ex vivo models of primary human cells and tissues through to pre-clinical models. This review consolidates our current understanding of how metabolic and cell signalling pathways triggered by poor glycaemic control, impact vascular function in diabetes. We also evaluate how these pathways could be exploited to develop targeted therapeutic approaches to improve cardiovascular outcomes specifically in people with diabetes. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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25 pages, 1697 KB

Open AccessReview

Critical Evaluation of the Role of Transcription Factor RAR-Orphan Receptor-γt in the Development of Chronic Inflammatory Dermatological Diseases: A Promising Therapeutic Target

by Anik Pramanik, Pallabi Mondal and Sankar Bhattacharyya

Biomolecules 2025, 15(11), 1543; https://doi.org/10.3390/biom15111543 - 2 Nov 2025

Nuclear receptors (NRs) are transcription factors regulated by ligands that direct metabolism, development, and immunity. The NR superfamily constitutes a principal category of pharmacological targets for human ailments. Retinoic acid receptor-related orphan receptors (RORs) α, β, and γ are part of the nuclear [...] Read more.

Nuclear receptors (NRs) are transcription factors regulated by ligands that direct metabolism, development, and immunity. The NR superfamily constitutes a principal category of pharmacological targets for human ailments. Retinoic acid receptor-related orphan receptors (RORs) α, β, and γ are part of the nuclear receptor superfamily. They are nevertheless classified as “orphan” receptors due to the contentious nature of identifying their endogenous ligands. RORγ nuclear receptor protein further consists of two isoforms, namely RORγ1 and RORγ2 or RORγt. RORγt is largely found in immune cells and has been primarily associated with chronic inflammatory conditions. The expression of STAT3 is a major driver of Th17 differentiation and induces RORγt expression through the JAK-STAT pathway. Type 3 innate lymphoid cells (ILC3s), Th17 cells, and γδT cells express RORγt, the master transcription regulator for the pro-inflammatory cytokine interleukin IL-17. In chronic inflammatory skin disorders, a significant increase in IL-17 has been observed, which plays a key role in both immune cell recruitment to the site of inflammation and the propagation of tissue damage. In this review, we will discuss how RORγt regulates IL-17-driven inflammation and explore potential strategies to target the RORγt-IL-17 axis as a viable therapeutic intervention in chronic inflammatory skin disorders. Full article

(This article belongs to the Special Issue Transcription Factors in Hematopoiesis and Immunity: From Development to Therapeutic Targeting)

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14 pages, 891 KB

Open AccessArticle

Within- and Between-Subject Analyses of the Effects of Chronic Xylazine on Negative Phototaxis in Two Planarian Species

by Tom Byrne

Biomolecules 2025, 15(11), 1542; https://doi.org/10.3390/biom15111542 - 2 Nov 2025

Xylazine, an adulterant found frequently in illicit fentanyl, has been implicated in causing several adverse effects in human recreational users, including skin lesions and complications in the treatment of opiate overdose. Despite these public health concerns, the literature on the basic behavioral effects [...] Read more.

Xylazine, an adulterant found frequently in illicit fentanyl, has been implicated in causing several adverse effects in human recreational users, including skin lesions and complications in the treatment of opiate overdose. Despite these public health concerns, the literature on the basic behavioral effects of xylazine is limited. Recent research has demonstrated that planarians show potential as an emerging and practical animal model for studying the behavioral effects of acute xylazine exposure. The goal of the current investigation was to evaluate the behavioral effects of chronic xylazine administration on negative phototaxis in two planarian species: Girardia tigrina and Schmidtea mediterranea. Three experiments were conducted. Overall, 10 µM of chronic xylazine exposure, arranged according to a multiple-baseline design, impaired negative phototaxis in S. mediterranea but not G. tigrina. An ABA reversal design indicated that behavioral effects in S. mediterranea abated when chronic xylazine was terminated. Finally, a between-group design replicated potential interspecies differences when G. tigrina and S. mediterranea were compared directly, with the latter showing significantly greater susceptibility to drug effects. This work provides evidence of the utility of a planarian model for studying the behavioral effects of xylazine and lays the foundation for further investigation into the chronic effects of the drug. Full article

(This article belongs to the Special Issue The Planarian Model in Pharmacology, Toxicology, and Neuroscience)

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27 pages, 2379 KB

Open AccessReview

Advances in Understanding Renin–Angiotensin System-Mediated Anti-Tumor Activity of Natural Polyphenols

by Ximing Wu, Mingchuan Yang, Hailing Zhang, Lumin Yang, Yufeng He, Xiaozhong Cheng and Guilan Zhu

Biomolecules 2025, 15(11), 1541; https://doi.org/10.3390/biom15111541 - 2 Nov 2025

The imbalance of the renin–angiotensin system (RAS), characterized by the overactivation of the pro-tumor ACE/AngII/AT1R axis, is closely linked to tumor growth, angiogenesis, metastasis, and poor prognosis. Natural polyphenols, such as EGCG and resveratrol, exert anti-cancer effects by dual-regulating RAS: they inhibit the [...] Read more.

The imbalance of the renin–angiotensin system (RAS), characterized by the overactivation of the pro-tumor ACE/AngII/AT1R axis, is closely linked to tumor growth, angiogenesis, metastasis, and poor prognosis. Natural polyphenols, such as EGCG and resveratrol, exert anti-cancer effects by dual-regulating RAS: they inhibit the pro-tumor axis by blocking renin, ACE activity, and AT1R expression, while simultaneously activating the protective ACE2/Ang(1-7)/MasR axis. Furthermore, polyphenols and their autoxidation products (e.g., EAOP) modify thiol-containing transmembrane proteins (such as ADAM17 and integrins) and interact with RAS components, further disrupting oncogenic pathways (including MAPK and PI3K/Akt/mTOR) to induce apoptosis, suppress invasion, and reduce oxidative stress. Notably, EAOP exhibits stronger RAS-modulating efficacy than its parent polyphenols. However, challenges such as low bioavailability, insufficient targeting, and limited clinical evidence impede their application. This review provides a comprehensive overview of the anti-cancer mechanisms of polyphenols through RAS regulation, discusses the associated challenges, and proposes potential solutions (including nanodelivery and structural modification) and strategies to advance natural product-based adjuvant treatments. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 4510 KB

Open AccessArticle

Hapten-Specific Cellular Immune Responses in the Elicitation and Sensitization Phases of Murine Contact Hypersensitivity

by Kornél Molnár, Gábor Kovács, Bence Kormos, Petra Aradi and Zoltán Jakus

Biomolecules 2025, 15(11), 1540; https://doi.org/10.3390/biom15111540 - 1 Nov 2025

Contact dermatitis (CD) is a common inflammatory skin condition with irritant etiology or a delayed-type hypersensitivity called allergic contact dermatitis (ACD). Contact hypersensitivity (CHS) is a widely used rodent model of ACD and similarly consists of two phases: sensitization and elicitation. To trigger [...] Read more.

Contact dermatitis (CD) is a common inflammatory skin condition with irritant etiology or a delayed-type hypersensitivity called allergic contact dermatitis (ACD). Contact hypersensitivity (CHS) is a widely used rodent model of ACD and similarly consists of two phases: sensitization and elicitation. To trigger CHS, low-molecular-weight haptens, such as DNFB or TNCB, are commonly applied. However, the characterization of the induced immune response remains incomplete. Our aim was to characterize the immune response after first and repeated exposures to model haptens. First exposure to DNFB or TNCB led to significant ear swelling, with DNFB causing a more pronounced effect. DNFB enhanced neutrophil infiltration, whereas TNCB led to macrophage, dendritic cell, and helper T cell accumulation. Repeated DNFB exposure did not aggravate edema significantly, while TNCB re-exposure enhanced edema formation and induced neutrophil granulocyte, dendritic cell, and helper and cytotoxic T cell accumulation. Our results demonstrate that a hapten-specific immune response is induced during both phases of CHS. A detailed understanding of allergen-specific immune responses is crucial for the appropriate selection of the model and for gaining deeper insight into the mechanisms of inflammatory skin diseases. These findings may contribute to the targeted selection of haptens. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 7749 KB

Open AccessArticle

Effects of Bile on Pathogenic Vibrio, Aeromonas, and Clostridioides spp. Toxin Effector Domains

by Jaylen E. Taylor, David B. Heisler, Eshan Choudhary, Elena Kudryashova and Dmitri S. Kudryashov

Biomolecules 2025, 15(11), 1539; https://doi.org/10.3390/biom15111539 - 1 Nov 2025

Bile acids, the primary components of bile, are cholesterol-derived molecules synthesized in the liver and secreted to the small intestine. Besides their primary digestive roles, bile acids have antimicrobial properties and serve as an environmental cue for intestinal pathogens, modulating the expression of [...] Read more.

Bile acids, the primary components of bile, are cholesterol-derived molecules synthesized in the liver and secreted to the small intestine. Besides their primary digestive roles, bile acids have antimicrobial properties and serve as an environmental cue for intestinal pathogens, modulating the expression of virulence factors, e.g., toxins and effector proteins. Whereas timely recognition and neutralization of pathogenic toxin effectors by the host is critical, our understanding of the effects of bile on their structure and function is limited. In this work, we found that bile effectively protected cultured IEC-18 enterocytes from the mixture of Aeromonas hydrophila secreted toxins, containing hemolysin, aerolysin, and RtxA (MARTX). To explore whether these effects have broad specificity, we employed biochemical and biophysical techniques to test the in vitro effects of bile and bile acids on several effector domains of MARTX and VgrG toxins from Vibrio cholerae and Aeromonas hydrophila, and catalytic domains of TcdA and TcdB toxins from Clostridioides difficile. Bile compromised the structural integrity of the tested effectors to various degrees in a protein charge-dependent manner. Bile and bile acids promoted exposure of hydrophobic residues and the unfolding of most, but not all, of the tested effectors, facilitating their precipitation and cleavage by chymotrypsin. Bile also inhibited specific activities of the tested effector enzymes, partially due to imposed oxidation of their catalytic residues. To summarize, this work validated bile as a non-proteinaceous factor of innate immunity, capable of compromising the structural integrity and function of the effector domains of various bacterial toxins. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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17 pages, 2960 KB

Open AccessArticle

Modeling the Mutational Effects on Biochemical Phenotypes of SARS-CoV-2 Using Molecular Fields

by Baifan Wang and Zhen Xi

Biomolecules 2025, 15(11), 1538; https://doi.org/10.3390/biom15111538 - 31 Oct 2025

The ongoing evolution of SARS-CoV-2 has given rise to variants with enhanced transmissibility and pathogenicity, many of which harbor mutations in the receptor-binding domain (RBD) of the viral spike protein. These mutations often confer increased viral fitness and immune evasion by modulating interactions [...] Read more.

The ongoing evolution of SARS-CoV-2 has given rise to variants with enhanced transmissibility and pathogenicity, many of which harbor mutations in the receptor-binding domain (RBD) of the viral spike protein. These mutations often confer increased viral fitness and immune evasion by modulating interactions with the human ACE2 receptor (hACE2) and escaping neutralizing antibodies. Accurate prediction of the functional consequences of such mutations—particularly their effects on receptor binding and antibody escape—is critical for assessing the public health threat posed by emerging variants. In this study, we apply a Mutation-dependent Biomacromolecular Quantitative Structure–Activity Relationship (MB-QSAR) framework to quantitatively model the biochemical phenotypes of RBD variants. Trained on comprehensive deep mutational scanning (DMS) datasets, our models exhibit strong predictive performance, achieving correlation coefficients (r²) exceeding 0.8 for hACE2 binding affinity and 0.7 for antibody neutralization escape. Importantly, the MB-QSAR approach generalizes well to multi-mutant variants and currently circulating lineages. Structural analysis based on model-derived interaction profiles offers mechanistic insights into key RBD–ACE2 and RBD–antibody interfaces, helping the rational design of broadly protective vaccines and therapeutics. This work establishes MB-QSAR as a rapid, accurate, and interpretable tool for the prediction of protein–protein interaction and forecasting viral adaptation, thereby facilitating early risk assessment of novel SARS-CoV-2 variants. Full article

(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)

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