Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Search Results (883)

Search Parameters:
Keywords = E3 ubiquitin ligases

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
17 pages, 16726 KiB  
Article
Genome-Wide Identification, Characterization, and Comparison of C3HC4 Family Genes in Salt Tolerance Between Barley and Rice
by Kerun Chen, Shuai Wang, Xiaohan Xu, Xintong Zheng, Hongkai Wu, Linzhou Huang, Liping Dai, Chenfang Zhan, Dali Zeng and Liangbo Fu
Plants 2025, 14(15), 2404; https://doi.org/10.3390/plants14152404 - 3 Aug 2025
Viewed by 260
Abstract
Soil salinization constitutes a major constraint on global agricultural production, with marked divergence in salt adaptation strategies between salt-tolerant barley (Hordeum vulgare) and salt-sensitive rice (Oryza sativa). This study systematically investigated the evolution and functional specialization of the C3HC4-type [...] Read more.
Soil salinization constitutes a major constraint on global agricultural production, with marked divergence in salt adaptation strategies between salt-tolerant barley (Hordeum vulgare) and salt-sensitive rice (Oryza sativa). This study systematically investigated the evolution and functional specialization of the C3HC4-type RING zinc finger gene family, known to mediate abiotic stress responses through E3 ubiquitin ligase activity, in these contrasting cereal species. Through comparative genomics, we identified 123 HvC3HC4 genes and 90 OsC3HC4 genes, phylogenetically classified into four conserved subgroups. Differences in C3HC4 genes in phylogenetic relationships, chromosomal distribution, gene structure, motif composition, gene duplication events, and cis-elements in the promoter region were observed between barley and rice. Moreover, HvC3HC4s in barley tissues preferentially adopted an energy-conserving strategy, which may be a key mechanism for barley’s higher salt tolerance. Additionally, we found that C3HC4 genes were evolutionarily conserved in salt-tolerant species. The current results reveal striking differences in salt tolerance between barley and rice mediated by the C3HC4 gene family and offer valuable insight for potential genetic engineering applications in improving crop resilience to salinity stress. Full article
(This article belongs to the Special Issue Cell Physiology and Stress Adaptation of Crops)
Show Figures

Figure 1

11 pages, 711 KiB  
Article
Cadmium Accumulation and Regulation in the Freshwater Mussel Anodonta woodiana
by Xiubao Chen, Chao Song, Jiazhen Jiang, Tao Jiang, Junren Xue, Ibrahim Bah, Mengying Gu, Meiyi Wang and Shunlong Meng
Toxics 2025, 13(8), 646; https://doi.org/10.3390/toxics13080646 - 30 Jul 2025
Viewed by 169
Abstract
Cadmium (Cd) pollution poses a serious threat to freshwater ecosystems. The freshwater mussel Anodonta woodiana is increasingly used as a bioindicator for monitoring Cd pollution in aquatic environments. However, the primary routes of Cd accumulation in A. woodiana remain unclear, and the molecular [...] Read more.
Cadmium (Cd) pollution poses a serious threat to freshwater ecosystems. The freshwater mussel Anodonta woodiana is increasingly used as a bioindicator for monitoring Cd pollution in aquatic environments. However, the primary routes of Cd accumulation in A. woodiana remain unclear, and the molecular regulatory mechanisms underlying Cd accumulation are poorly understood. To address these gaps, this study employed a novel stable isotope dual-tracer technique to trace Cd from water (waterborne 112Cd) and the green alga Chlorella vulgaris (dietary 113Cd) during the simultaneous exposure experiment. Comparative transcriptomic analysis was then conducted to characterize molecular responses in A. woodiana following Cd exposure. The results showed that although newly accumulated 112Cd and 113Cd increased with exposure concentration and duration, the relative importance of 112Cd (91.6 ± 2.8%) was significantly higher than that of 113Cd (8.4 ± 2.8%) (p < 0.05). Cd exposure induced differentially expressed genes primarily enriched in the metabolic processes, cellular processes, and/or the ubiquitin-mediated proteolysis pathway. Within the ubiquitin-mediated proteolysis pathway, TRIP12 (E3 ubiquitin-protein ligase TRIP12) and Cul5 (cullin-5) were significantly upregulated. The findings will provide critical insights for interpreting Cd biomonitoring data in freshwater environments using mussels as bioindicators. Full article
(This article belongs to the Special Issue The Impact of Heavy Metals on Aquatic Ecosystems)
Show Figures

Figure 1

25 pages, 4337 KiB  
Article
Cullin-3 and Regulatory Biomolecules Profiling in Vitiligo: Integrated Docking, Clinical, and In Silico Insights
by Hidi A. A. Abdellatif, Mohamed Azab, Eman Hassan El-Sayed, Rwan M. M. M. Halim, Ahmad J. Milebary, Dhaifallah A. Alenizi, Manal S. Fawzy and Noha M. Abd El-Fadeal
Biomolecules 2025, 15(7), 1053; https://doi.org/10.3390/biom15071053 - 21 Jul 2025
Viewed by 394
Abstract
Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 [...] Read more.
Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 degradation, and its interplay with inflammatory mediators in vitiligo pathogenesis are underexplored. This study investigates CUL3, NRF2, and the associated regulatory networks in vitiligo, integrating clinical profiling and computational docking to identify therapeutic targets. Methods: A case-control study compared non-segmental vitiligo patients with age-/sex-matched controls. Lesional skin biopsies were analyzed by qRT-PCR for the expression of CUL3, NRF2, miRNA-146a, FOXP3, NF-κB, IL-6, TNF-α, and P53. Molecular docking was used to evaluate vitexin’s binding affinity to Keap1, validated by root mean square deviation (RMSD) calculations. Results: Patients with vitiligo exhibited significant downregulation of CUL3 (0.27 ± 0.03 vs. 1 ± 0.58; p = 0.013), NRF2 (0.37 ± 0.26 vs. 1 ± 0.8; p = 0.001), and FOXP3 (0.09 ± 0.2 vs. 1 ± 0.3; p = 0.001), alongside the upregulation of miRNA-146a (4.7 ± 1.9 vs. 1 ± 0.8; p = 0.001), NF-κB (4.7 ± 1.9 vs. 1 ± 0.5; p = 0.001), IL-6 (2.8 ± 1.5 vs. 1 ± 0.4; p = 0.001), and TNF-α (2.2 ± 1.1 vs. 1 ± 0.3; p = 0.001). P53 showed no differential expression (p > 0.05). Docking revealed a strong binding of vitexin to Keap1 (RMSD: 0.23 Å), mirroring the binding of the control ligand CDDO-Im. Conclusions: Dysregulation of the CUL3/Keap1/NRF2 axis and elevated miRNA-146a levels correlate with vitiligo progression, suggesting a role for oxidative stress and immune imbalance. Vitexin’s high-affinity docking to Keap1 positions it as a potential modulator of the NRF2 pathway, offering novel therapeutic avenues. This study highlights the translational potential of targeting the ubiquitin–proteasome and antioxidant pathways in the management of vitiligo. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Skin Disorders)
Show Figures

Figure 1

25 pages, 6270 KiB  
Article
Ethanolic Extract of Glycine Semen Preparata Prevents Oxidative Stress-Induced Muscle Damage in C2C12 Cells and Alleviates Dexamethasone-Induced Muscle Atrophy and Weakness in Experimental Mice
by Aeyung Kim, Jinhee Kim, Chang-Seob Seo, Yu Ri Kim, Kwang Hoon Song and No Soo Kim
Antioxidants 2025, 14(7), 882; https://doi.org/10.3390/antiox14070882 - 18 Jul 2025
Viewed by 461
Abstract
Skeletal muscle atrophy is a debilitating condition characterized by the loss of muscle mass and function. It is commonly associated with aging, chronic diseases, disuse, and prolonged glucocorticoid therapy. Oxidative stress and catabolic signaling pathways play significant roles in the progression of muscle [...] Read more.
Skeletal muscle atrophy is a debilitating condition characterized by the loss of muscle mass and function. It is commonly associated with aging, chronic diseases, disuse, and prolonged glucocorticoid therapy. Oxidative stress and catabolic signaling pathways play significant roles in the progression of muscle degradation. Despite its clinical relevance, few effective therapeutic options are currently available. In this study, we investigated the protective effects of an ethanolic extract of Glycine Semen Preparata (GSP), i.e., fermented black soybeans, using in vitro and in vivo models of dexamethasone (Dexa)-induced muscle atrophy. In C2C12 myoblasts and myotubes, GSP significantly attenuated both oxidative stress-induced and Dexa-induced damages by reducing reactive oxygen species levels and by suppressing the expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1. Moreover, GSP upregulated key genes involved in muscle regeneration (Myod1 and Myog) and mitochondrial biogenesis (PGC1α), indicating its dual role in muscle protection and regeneration. Oral administration of GSP to mice with Dexa-induced muscle atrophy resulted in improved muscle fiber integrity, increased proportion of large cross-sectional area fibers, and partial recovery of motor function. Isoflavone aglycones, such as daidzein and genistein, were identified as active compounds that contribute to the beneficial effects of GSP through antioxidant activity and gene promoter enhancement. Thus, GSP is a promising nutraceutical that prevents or mitigates muscle atrophy by targeting oxidative stress and promoting myogenesis and mitochondrial function. Further studies are warranted to standardize the bioactive components and explore their clinical applications. Full article
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
Show Figures

Graphical abstract

21 pages, 1099 KiB  
Review
The Roles of E3 Ubiquitin Ligases in Cerebral Ischemia–Reperfusion Injury
by Man Li, Xiaoxiao Yu, Qiang Liu, Zhi Fang and Haijun Wang
Int. J. Mol. Sci. 2025, 26(14), 6723; https://doi.org/10.3390/ijms26146723 - 13 Jul 2025
Viewed by 342
Abstract
The temporary or permanent occlusion of cerebral blood vessels results in ischemic stroke (IS). Ischemia per se causes focal neuronal damage, and the subsequent ischemia–reperfusion injury that occurs after blood flow restoration further compromises brain tissue and cells in the neurovascular unit, significantly [...] Read more.
The temporary or permanent occlusion of cerebral blood vessels results in ischemic stroke (IS). Ischemia per se causes focal neuronal damage, and the subsequent ischemia–reperfusion injury that occurs after blood flow restoration further compromises brain tissue and cells in the neurovascular unit, significantly contributing to poor patient outcomes and functional impairments. Current research indicates that the ubiquitin–proteasome system (UPS) plays a crucial role in the pathological processes associated with cerebral ischemia–reperfusion injury (CIRI). Notably, E3 ubiquitin (Ub) ligases, which are essential in the UPS, have garnered increasing attention as potential novel therapeutic targets for treating ischemia–reperfusion damage in the brain. This review focuses primarily on the background of E3 Ub ligases and explores their intricate relationships with the pathological processes of CIRI. Full article
(This article belongs to the Special Issue Latest Advances in Oxidative Stress and Brain Injury)
Show Figures

Figure 1

21 pages, 7262 KiB  
Article
Integrative Multi-Omics Analysis Reveals the Molecular Characteristics, Tumor Microenvironment, and Clinical Significance of Ubiquitination Mechanisms in Lung Adenocarcinoma
by Deyu Long, Yajing Xue, Xiushi Yu, Xue Qin, Jiaxin Chen, Jia Luo, Ketao Ma, Lili Wei and Xinzhi Li
Int. J. Mol. Sci. 2025, 26(13), 6501; https://doi.org/10.3390/ijms26136501 - 6 Jul 2025
Viewed by 499
Abstract
Ubiquitination is a dynamic and reversible post-translational modification mediated by ubiquitination regulators (UBRs), which plays an essential role in protein stability, cell differentiation and immunity. Dysregulation of UBRs can lead to destabilization of biological processes and may induce serious human diseases, including cancer. [...] Read more.
Ubiquitination is a dynamic and reversible post-translational modification mediated by ubiquitination regulators (UBRs), which plays an essential role in protein stability, cell differentiation and immunity. Dysregulation of UBRs can lead to destabilization of biological processes and may induce serious human diseases, including cancer. Many UBRs, such as E3 ubiquitin ligases and deubiquitinases (DUBs), have been identified as potential drug targets for cancer therapy. However, the potential clinical value of UBRs in lung adenocarcinoma (LUAD) remains to be elucidated. Here, we identified 17 hub UBRs from high-confidence protein–protein interaction networks of UBRs correlated with cancer hallmark-related pathways using four topological algorithms. The expression of hub UBRs is affected by copy number variation and post-transcriptional regulation, and their high expression is often detrimental to patient survival. Based on the expression profiles of hub UBRs, patients can be classified into two ubiquitination subtypes with different characteristics. These subtypes exhibit significant differences across multiple dimensions, including survival, expression level, mutation burden, female predominance, infiltration level, immune profile, and drug response. In addition, we established a scoring system for evaluating the ubiquitination status of individual LUAD patients, called the ubiquitination-related risk (UB_risk) score, and found that patients with low scores are more likely to gain advantages from immunotherapy. The results of this study emphasize the critical role of ubiquitination in the classification, tumor microenvironment and immunotherapy of LUAD. The construction of the UB_risk scoring system lays a research foundation for evaluating the ubiquitination status of individual LUAD patients and formulating precise treatment strategies from the ubiquitination level. Full article
(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)
Show Figures

Figure 1

17 pages, 5007 KiB  
Review
PROTAC-Based Antivirals for Respiratory Viruses: A Novel Approach for Targeted Therapy and Vaccine Development
by Amith Anugu, Pankaj Singh, Dharambir Kashyap, Jillwin Joseph, Sheetal Naik, Subhabrata Sarkar, Kamran Zaman, Manpreet Dhaliwal, Shubham Nagar, Tanishq Gupta and Prasanna Honnavar
Microorganisms 2025, 13(7), 1557; https://doi.org/10.3390/microorganisms13071557 - 2 Jul 2025
Viewed by 520
Abstract
The global burden of respiratory viral infections is notable, which is attributed to their higher transmissibility compared to other viral diseases. Respiratory viruses are seen to have evolved resistance to available treatment options. Although vaccines and antiviral drugs control some respiratory viruses, this [...] Read more.
The global burden of respiratory viral infections is notable, which is attributed to their higher transmissibility compared to other viral diseases. Respiratory viruses are seen to have evolved resistance to available treatment options. Although vaccines and antiviral drugs control some respiratory viruses, this control is limited due to unexpected events, such as mutations and the development of antiviral resistance. The technology of proteolysis-targeting chimeras (PROTACs) has been emerging as a novel technology in viral therapeutics. These are small molecules that can selectively degrade target proteins via the ubiquitin–proteasome pathway. PROTACs as a therapy were initially developed against cancer, but they have recently shown promising results in their antiviral mechanisms by targeting viral and/or host proteins involved in the pathogenesis of viral infections. In this review, we elaborate on the antiviral potential of PROTACs as therapeutic agents and their potential as vaccine components against important respiratory viral pathogens, including influenza viruses, coronaviruses (SARS-CoV-2), and respiratory syncytial virus. Advanced applications of PROTAC antiviral strategies, such as hemagglutinin and neuraminidase degraders for influenza and spike proteins of SARS-CoV-2, are detailed in this review. Additionally, the role of PROTACs in targeting cellular mechanisms within the host, thereby preventing viral pathogenesis and eliciting an antiviral effect, is discussed. The potential of PROTACs as vaccines, utilizing proteasome-based virus attenuation to achieve a robust protective immune response, while ensuring safety and enhancing efficient production, is also presented. With the promises exhibited by PROTACs, this technology faces significant challenges, including the emergence of novel viral strains, tissue-specific expression of E3 ligases, and pharmacokinetic constraints. With advanced computational design in molecular platforms, PROTAC-based antiviral development offers an alternative, transformative path in tackling respiratory viruses. Full article
Show Figures

Figure 1

18 pages, 1248 KiB  
Article
Exploring the Role of Oleic Acid in Muscle Cell Differentiation: Mechanisms and Implications for Myogenesis and Metabolic Regulation in C2C12 Myoblasts
by Francesco Vari, Elisa Bisconti, Ilaria Serra, Eleonora Stanca, Marzia Friuli, Daniele Vergara and Anna Maria Giudetti
Biomedicines 2025, 13(7), 1568; https://doi.org/10.3390/biomedicines13071568 - 26 Jun 2025
Viewed by 509
Abstract
Background/Objectives: Myogenesis, the process by which myoblasts differentiate into multinucleated muscle fibers, is tightly regulated by transcription factors, signaling pathways, and metabolic cues. Among these, fatty acids have emerged as key regulators beyond their traditional role as energy substrates. Oleic acid, a [...] Read more.
Background/Objectives: Myogenesis, the process by which myoblasts differentiate into multinucleated muscle fibers, is tightly regulated by transcription factors, signaling pathways, and metabolic cues. Among these, fatty acids have emerged as key regulators beyond their traditional role as energy substrates. Oleic acid, a monounsaturated fatty acid, has been shown to modulate muscle differentiation, potentially influencing myogenic pathways. This study examines the role of oleic acid in promoting C2C12 myoblast differentiation and its associated molecular mechanisms, comparing it to standard horse serum (HS)-based differentiation protocols. Methods: C2C12 murine myoblasts were cultured under proliferative conditions and differentiated using DMEM supplemented with either 2% HS or oleic acid (C18:1, n-9). The molecular signaling pathway was evaluated by measuring the expression of p38 MAPK, β-catenin, GLUT4, and NDRG1. Results: Oleic acid promoted the differentiation of C2C12 cells, as evidenced by a progressively elongated morphology, as well as the induction of muscle-specific myogenin, myosin heavy chain (MHC), and MyoD. Moreover, oleic acid reduced the expression of Atrogin-1 and MuRF1 ubiquitin E3 ligase. BODIPY staining revealed the enhanced accumulation of lipid droplets in oleic acid-treated cells. The Western blot analysis demonstrated robust activation of p38 MAPK and β-catenin pathways in response to oleic acid, compared with HS. Additionally, oleic acid upregulated GLUT4 expression and increased the phosphorylation of insulin receptor and NDRG1, indicating an enhanced glucose uptake capacity. Conclusions: These findings demonstrate that oleic acid promotes C2C12 myoblast differentiation and improves glucose uptake via GLUT4. Oleic acid emerges as a promising metabolic regulator of myogenesis, offering potential therapeutic applications for muscle regeneration in muscle-related pathologies. Full article
(This article belongs to the Section Cell Biology and Pathology)
Show Figures

Figure 1

18 pages, 2646 KiB  
Article
COP1 Deficiency in BRAFV600E Melanomas Confers Resistance to Inhibitors of the MAPK Pathway
by Ada Ndoja, Christopher M. Rose, Eva Lin, Rohit Reja, Jelena Petrovic, Sarah Kummerfeld, Andrew Blair, Helen Rizos, Zora Modrusan, Scott Martin, Donald S. Kirkpatrick, Amy Heidersbach, Tao Sun, Benjamin Haley, Ozge Karayel, Kim Newton and Vishva M. Dixit
Cells 2025, 14(13), 975; https://doi.org/10.3390/cells14130975 - 25 Jun 2025
Viewed by 707
Abstract
Aberrant activation of the mitogen-activated protein kinase (MAPK) cascade promotes oncogenic transcriptomes. Despite efforts to inhibit oncogenic kinases, such as BRAFV600E, tumor responses in patients can be heterogeneous and limited by drug resistance mechanisms. Here, we describe patient tumors that acquired COP1 or [...] Read more.
Aberrant activation of the mitogen-activated protein kinase (MAPK) cascade promotes oncogenic transcriptomes. Despite efforts to inhibit oncogenic kinases, such as BRAFV600E, tumor responses in patients can be heterogeneous and limited by drug resistance mechanisms. Here, we describe patient tumors that acquired COP1 or DET1 mutations after treatment with the BRAFV600E inhibitor vemurafenib. COP1 and DET1 constitute the substrate adaptor of the E3 ubiquitin ligase CRL4COP1/DET1, which targets transcription factors, including ETV1, ETV4, and ETV5, for proteasomal degradation. MAPK-MEK-ERK signaling prevents CRL4COP1/DET1 from ubiquitinating ETV1, ETV4, and ETV5, but the mechanistic details are still being elucidated. We found that patient mutations in COP1 or DET1 inactivated CRL4COP1/DET1 in melanoma cells, stabilized ETV1, ETV4, and ETV5, and conferred resistance to inhibitors of the MAPK pathway. ETV5, in particular, enhanced cell survival and was found to promote the expression of the pro-survival gene BCL2A1. Indeed, the deletion of pro-survival BCL2A1 re-sensitized COP1 mutant cells to vemurafenib treatment. These observations indicate that the post-translational regulation of ETV5 by CRL4COP1/DET1 modulates transcriptional outputs in ERK-dependent cancers, and its inactivation contributes to therapeutic resistance. Full article
(This article belongs to the Special Issue Targeting Hallmarks of Cancer)
Show Figures

Graphical abstract

7 pages, 1795 KiB  
Commentary
The Ac/N-Degron Domain of MARCHF6 E3 Ubiquitin Ligase and Its Role in Regulating Ferroptosis
by Hope Omoniyi, Grace Hohman and Mohamed Eldeeb
Cells 2025, 14(13), 954; https://doi.org/10.3390/cells14130954 - 22 Jun 2025
Viewed by 514
Abstract
Ferroptosis is a form of cell death characterized by iron and reactive oxygen species accumulation. Notably, this mode of cell death has been shown to exhibit significant implications for aging-related disorders including tumorigenesis and neurodegeneration. Nonetheless, the intricate underlying molecular mechanisms of ferroptosis [...] Read more.
Ferroptosis is a form of cell death characterized by iron and reactive oxygen species accumulation. Notably, this mode of cell death has been shown to exhibit significant implications for aging-related disorders including tumorigenesis and neurodegeneration. Nonetheless, the intricate underlying molecular mechanisms of ferroptosis and their differential roles in the molecular etiology of these diseases are still elusive. Elucidating the precise molecular mechanisms underlying ferroptosis is, thus, important for understanding the molecular basis of these diseases and unveiling potential therapeutic targets. MARCHF6 is an E3 ub ligase involved in regulating various cellular processes throughout the cell including ferroptosis. Research findings by Yang et al. identified a novel role of MARCHF6 E3 ub ligase in recognizing Ac/N-degron bearing substrates, which includes pro-ferroptotic and anti-ferroptotic proteins, demonstrating a regulatory role for MARCHF6 in fine-tuning ferroptosis. Herein, we highlight these recent findings and discuss the potential role of MARCHF6 in modulating ferroptosis pointing to the emerging role of MARCHF6 as a potential therapeutic target for treating ferroptosis-related diseases. Full article
Show Figures

Figure 1

63 pages, 3732 KiB  
Review
TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease
by Ana Luísa Rodriguez Gini, Pamela Souza Tada da Cunha, Emílio Emílio João, Chung Man Chin, Jean Leandro dos Santos, Esteban Carlos Serra and Cauê Benito Scarim
Pharmaceuticals 2025, 18(6), 919; https://doi.org/10.3390/ph18060919 - 19 Jun 2025
Viewed by 1387
Abstract
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel [...] Read more.
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel therapeutic avenue by leveraging the ubiquitin–proteasome system to selectively degrade essential parasite proteins. This review introduces the conceptual framework of “TrypPROTACs” as a prospective strategy for T. cruzi, integrating a comprehensive analysis of druggable targets across critical biological pathways, including ergosterol biosynthesis, redox metabolism, glycolysis, nucleotide synthesis, protein kinases, molecular chaperones such as heat shock protein 90 (Hsp90), and epigenetic regulators such as T. cruzi bromodomain factor 3 (TcBDF3). It is important to note that no TrypPROTAC compound has yet been synthesized or experimentally validated in T. cruzi; the approach discussed herein remains theoretical and forward-looking. Representative inhibitors for each target class are compiled, highlighting potency, selectivity, and structural features relevant to ligand design. We also examine the parasite’s ubiquitination machinery and compare it to the human system to identify putative E3 ubiquitin ligases. Key aspects of linker engineering and ternary complex stabilization are discussed, alongside potential validation techniques such as the cellular thermal shift assay (CETSA) and bioluminescence resonance energy transfer (NanoBRET). Collectively, these insights outline a roadmap for the rational design of TrypPROTACs and support the feasibility of expanding targeted protein degradation strategies to neglected tropical diseases. Full article
Show Figures

Graphical abstract

18 pages, 1236 KiB  
Review
Molecular Mechanisms of Cadmium Stress Resistance in Vegetable Crops
by Mengxia Zhang and Chunjuan Dong
Int. J. Mol. Sci. 2025, 26(12), 5812; https://doi.org/10.3390/ijms26125812 - 17 Jun 2025
Viewed by 501
Abstract
Cadmium (Cd) stress poses significant threats to vegetable crops, impacting their growth, physiological processes, and safety as part of the human food chain. This review systematically summarizes the latest advances in the molecular mechanisms of vegetable crops’ resistance to Cd stress. First, physiological [...] Read more.
Cadmium (Cd) stress poses significant threats to vegetable crops, impacting their growth, physiological processes, and safety as part of the human food chain. This review systematically summarizes the latest advances in the molecular mechanisms of vegetable crops’ resistance to Cd stress. First, physiological and biochemical responses are outlined, including growth inhibition, impaired photosynthesis, oxidative stress, disrupted nutrient absorption, altered phytohormone levels, and gene expression changes. Next, key molecular mechanisms are discussed, focusing on the roles of transporter-related genes (e.g., NRAMP, HIPP, ABCG), transcription factors (e.g., HsfA1a, WRKY, ERF), enzyme-related genes (e.g., E3 ubiquitin ligase, P-type ATPase), microRNAs (e.g., miR398), and potential functional genes in Cd uptake, translocation, and detoxification. Additionally, the regulatory roles of phytohormones and their analogues (e.g., brassinosteroids, gibberellin, salicylic acid) in mitigating Cd toxicity are analyzed, highlighting their involvement in antioxidant defense, gene regulation, and stress signaling pathways. Finally, future research directions are proposed, emphasizing species-specific defense mechanisms, root hair-specific Cd exclusion mechanisms, and interdisciplinary approaches integrating AI and microbiome manipulation. This review provides a comprehensive reference for enhancing Cd stress resistance in vegetable crops and promoting safe crop production. Full article
(This article belongs to the Special Issue Advanced Plant Molecular Responses to Abiotic Stresses)
Show Figures

Figure 1

20 pages, 6736 KiB  
Article
Genome-Wide Identification, Characterization, and Expression Analysis of the U-Box Gene Family in Cucumber (Cucumis sativus)
by Quanqing Chen, Tian Zhao, Hao Song, Siyuan Sha, Jun Ma, Ruihan Zhang, Weiwen Kong, Shuying Yang, Jinglan Liu and Yiping Wang
Plants 2025, 14(12), 1801; https://doi.org/10.3390/plants14121801 - 12 Jun 2025
Viewed by 571
Abstract
Plant U-box (PUB) E3 ubiquitin ligases have undergone significant expansion compared to their fungal and animal counterparts. These E3 ligases play critical roles in diverse biological processes, including responses to biotic and abiotic stresses. However, systematic identification of PUB genes in cucumber ( [...] Read more.
Plant U-box (PUB) E3 ubiquitin ligases have undergone significant expansion compared to their fungal and animal counterparts. These E3 ligases play critical roles in diverse biological processes, including responses to biotic and abiotic stresses. However, systematic identification of PUB genes in cucumber (Cucumis sativus L.) has been lacking, and their expression and functional characterization remain largely unexplored. Leveraging the recently released near-complete cucumber genome, we identified 53 putative PUB proteins classified into eight distinct groups based on domain architecture. The molecular weights of CsPUBs range from 26 to 166 kilodaltons (kDa). Exon numbers in CsPUB genes vary substantially, with CsPUB48 containing a maximum of 17 exons, while 18 CsPUB genes harbor only a single exon. Chromosomal distribution of CsPUBs is uneven, with Chr 3 harboring the highest density (12 genes) and Chr 7 the lowest (1 gene). Notably, tandem duplications (e.g., CsPUB29-CsPUB36 and CsPUB18-CsPUB49) and seven collinear gene pairs were identified, suggesting evolutionary diversification. Promoter regions of CsPUBs are enriched with cis-regulatory elements linked to plant growth and development, phytohormone, stress responses, light, and so on, implying their regulatory roles in various biological processes. Expression profiling revealed tissue-specific patterns and differential regulation of multiple CsPUBs under stress conditions. Subcellular localization studies demonstrated that CsPUBs target diverse organelles, with some localizing to punctate structures potentially representing uncharacterized compartments. Collectively, this systematic analysis establishes a comprehensive framework for understanding particular CsPUB functions. Full article
(This article belongs to the Section Plant Genetics, Genomics and Biotechnology)
Show Figures

Figure 1

20 pages, 2505 KiB  
Review
Emerging Concepts of Targeted Protein Degrader Technologies via Lysosomal Pathways
by Mohammad Maqusood Alam, Sobia Wasim and Sang-Yoon Lee
Int. J. Mol. Sci. 2025, 26(12), 5582; https://doi.org/10.3390/ijms26125582 - 11 Jun 2025
Viewed by 1035
Abstract
Targeted protein degradation (TPD) has emerged as a revolutionary strategy for modulating protein function, offering a promising alternative to traditional small-molecule inhibitors. The distinctive mechanism of action in TPD has previously allowed researchers to target undruggable proteins, broadening the scope of “druggable” properties [...] Read more.
Targeted protein degradation (TPD) has emerged as a revolutionary strategy for modulating protein function, offering a promising alternative to traditional small-molecule inhibitors. The distinctive mechanism of action in TPD has previously allowed researchers to target undruggable proteins, broadening the scope of “druggable” properties and expanding the scope of therapeutic possibilities. As the field of TPD advances, several alternative strategies to proteolysis-targeting chimeras (PROTACs) have emerged, which do not rely on the E3 ubiquitin ligase recruitment mechanism, expending the scope of TPD. Recently, several new technologies have emerged for TPD of extracellular and membrane proteins. While encouraging progress has been made in this field, the application of these technologies remains in its early stages. In this review, we explore the therapeutic potential of current key emerging lysosome-mediated TPD approaches by summarizing key discoveries and address the challenges associated with degrading extracellular and membrane protein targets. We also outline the chemical structure, activity, and pharmaceutical properties of each degrader, as well as the development of chemical probes for perturbing autophagy pathways. Full article
(This article belongs to the Section Molecular Pharmacology)
Show Figures

Figure 1

23 pages, 4360 KiB  
Article
Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules
by Naeyma N. Islam and Thomas R. Caulfield
Biomolecules 2025, 15(6), 849; https://doi.org/10.3390/biom15060849 - 10 Jun 2025
Cited by 1 | Viewed by 1063
Abstract
Alzheimer’s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Aβ42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Aβ42 as an early and toxic driver of disease progression. In this study, we [...] Read more.
Alzheimer’s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Aβ42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Aβ42 as an early and toxic driver of disease progression. In this study, we present a novel, Generative AI–based drug design approach to promote targeted degradation of Aβ42 via the ubiquitin–proteasome system (UPS), using E3 ligase–directed molecular glues. We systematically evaluated the ternary complex formation potential of Aβ42 with three E3 ligases (CRBN, VHL, and MDM2) through structure-based modeling, ADMET screening, and docking. We then developed a Ligase-Conditioned Junction Tree Variational Autoencoder (LC-JT-VAE) to generate ligase-specific small molecules, incorporating protein sequence embeddings and torsional angle-aware molecular graphs. Our results demonstrate that this generative model can produce chemically valid, novel, and target-specific molecular glues capable of facilitating Aβ42 degradation. This integrated approach offers a promising framework for designing UPS-targeted therapies for neurodegenerative diseases. Full article
Show Figures

Figure 1

Back to TopTop