Search Results (157)

Background: Keloid scarring is a fibroproliferative disorder driven by a complex interplay of genetic, epigenetic, and environmental factors, resulting in significant cosmetic and functional impairment. Despite its high prevalence in African, Asian, and Hispanic populations, the molecular mechanisms underlying ancestry-dependent susceptibility remain incompletely understood. Methods: This narrative review synthesizes current genomic, epigenetic, and multi-omic evidence related to keloid scarring. Relevant literature was identified through a targeted, structured, non-systematic search of PubMed, Scopus, Web of Science, SciELO, and Google Scholar up to August 2025, focusing on genetic susceptibility loci, epigenetic regulation, and ancestry-related differences. PRISMA-ScR guidelines were used as a reporting framework to enhance transparency, without implying a formal systematic review methodology. Results: This synthesis identifies recurrent susceptibility loci at 1q41, 3q22.3, and 15q21.3 across multiple populations. Variants in NEDD4 and regulatory regions near BMP2 emerge as key modulators of profibrotic signaling pathways, including TGF-β/SMAD and NF-κB. Additionally, epigenetic reprogramming and long non-coding RNA networks, such as CACNA1G-AS1, appear to sustain fibroblast hyperactivation. A persistent limitation is the marked underrepresentation of Latin American populations in current genomic studies. Conclusions: Integrating ancestry-specific genomic variation with epigenetic markers is essential for advancing precision diagnostic and therapeutic strategies in keloid scarring. Future research should prioritize diverse, multicenter cohorts and integrative multi-omics approaches to improve risk stratification and enable targeted interventions for this disfiguring condition. Full article

Background: The Xinjiang Black pig is an excellent breed developed by the Xinjiang Production and Construction Corps in the 1990s; however, it has been endangered by the impact of commercial breeds. Methods: Whole genomes of 224 individuals from the Xinjiang Black pig conservation population were resequenced. Results: Genetic structure and diversity analyses revealed that Xinjiang Black pigs underwent severe inbreeding and were genetically closely linked to Landrace pigs. The genetic diversity of the F₂ generation was well preserved in the existing breeding scheme. A total of 686 significant selection regions and 406 candidate genes were identified using F_ST and θπ complementary methods, with Xinjiang Black pigs, Min pigs, and Laiwu pigs as ancestral populations, and F₂. Based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and quantitative trait loci annotations, potential germplasm candidate genes were identified. Among these, SOX5, HMG20A, and NEDD4 are associated with fat deposition; SPRY1, MNS1, DMXL2, and ALB are closely associated with male reproductive ability; ARPP19 and TLN2 are strongly associated with oestrous cycle regulation and oocyte maturation; and SLC4A4 and SLC12A1 are extremely important for osmotic regulation and foetal survival. Conclusions: These findings deepen our understanding of the genetic mechanisms of artificial selection in Xinjiang Black pigs and provide a theoretical basis for subsequent breeding and genetic research on this breed. Full article

With the rapid development of genomic big data and genome-wide association study technologies, massive genomic data are available for the genetic dissection, development and utilization of important economic traits. Various GWAS algorithms have become increasingly efficient, enabling high-performance processing of these massive datasets. This has made it possible to conduct genetic dissection of economic traits based on big data and advanced statistical methods, which will provide accurate target loci for future trait improvement and genetic manipulation, greatly accelerating the process of genetic breeding. In this study, genotyping of 426 fish was performed using the T7 sequencing platform and 555,242 SNPs distributed across all the chromosomes were screened by data cleaning. We compared the performance of two GWAS methods, GCTA and GEMMA, in both single-trait and multi-trait frameworks. Twenty-nine SNPs significantly associated with seven traits were identified through single and multi-trait combined GWAS. Single-trait GWAS analysis using GCTA identified 1047 and 1452 significant loci for six growth traits and one sex trait (phenotypic sex, male or female) respectively, ultimately revealing 10 candidate genes, including slc48a1a, filip1L, nedd9, Crebbpa, LOC134024622, zbtb18, LOC117378376, LOC131530706, syde2, and col24a1. Similarly, 671 and 642 significant SNPs were detected with GEMMA for single-trait GWAS associated with six growth traits and the sex trait, respectively. In total, 16 candidate genes were mapped for these seven traits. Multi-trait GWAS was also performed using GEMMA for the six growth traits (sex was included as a covariate). The traits were grouped into five combinations based on their genetic correlations. A total of 37 SNPs were identified, corresponding to 10 candidate genes: LOC131530706, LOC134022516, abat, maml3, cica, LOC124013321, slc25a12, dnah10, syt9a, and LOC136932979. Notably, five overlapping candidate genes (LOC131530706, LOC134022516, abat, slc25a12 and dnah10) were also identified in both single- and multi-trait GWAS methods of GEMMA, highlighting their genetic stability and significance. The two GWAS methods, GCTA and GEMMA, identified two genes that were the same. The results of this study provide molecular markers and genetic resources for the improvement of growth traits in Plecoglossus altivelis. Full article

Background: Long INterspersed Element-1 (LINE-1) retrotransposons comprise 17–20% of the human genome. These retroelements are normally silenced early in embryonic development through epigenetic mechanisms and reawakened during oncogenesis, leading to transcriptional dysregulation, genomic instability, and immune evasion. Methods: In the present study, we categorized LINE-1 transcripts across 121 non-small cell lung cancer (NSCLC) cell lines from the Cancer Cell Line Encyclopedia (CCLE) by subfamily, length, orientation, chromosomal origin, and distribution. In addition, high-prevalence insertions were mapped to nearby genes to assess potential functional interactions. Results: LINE-1 transcript abundance and length in NSCLC were dominated by evolutionarily young subfamilies, particularly L1HS and L1PA2 through L1PA5. Chromosomal patterns were conserved across NSCLC subtypes, with modest enrichment of L1HS activity on Chromosome 4 and the X Chromosome. The lung squamous cell carcinoma (LSQCC) subtype exhibited the highest total levels of L1HS expression relative to other NSCLC subtypes. Race modestly influenced LINE-1 transcript abundance, with cell lines derived from self-identified African American individuals showing elevated overall LINE-1 and L1HS expression. Age showed a weak positive correlation with total LINE-1 abundance. Integrative analysis revealed recurrent hotspots at 22q12.1 and 20p11.21 that were transcriptionally active across subtypes and coincided with previously reported intact LINE-1 elements active in epithelial cancers. Recurrent insertions were located near cancer-associated genes, including RB1, NEDD4, FTO, LAMA2, NOD1, and KCNB2, implicating LINE-1 activity in cis-regulatory remodeling of oncogenic pathways. Conclusions: Together, these findings indicate that LINE-1 transcript heterogeneity in NSCLC is shaped by host genomic architecture and conserved functional hotspots, providing new insights into the mechanisms of genetic and epigenetic dysregulation associated with LINE-1 retroelements. Full article

Idiopathic pulmonary fibrosis is a chronic, progressive, interstitial lung disease for which specific and effective drug therapies are still lacking. Lathyrol is a diterpene compound with broad pharmacological activities that can be extracted from the traditional Chinese medicine Leptochloa chinensis (L.) Nees. To investigate the anti-pulmonary fibrosis effect of lathyrol and its underlying mechanism. In vivo, a mouse model of pulmonary fibrosis was induced by bleomycin, treated with intraperitoneal injections of lathyrol. In vitro, myofibroblast conversion was induced in three fibroblast cell lines by stimulating them with TGF-β1, followed by treatment with lathyrol. Transcriptomic analysis was performed to assess the regulation of signaling pathways and gene expression patterns modulated by lathyrol. The effects of lathyrol on PPARγ activation, as well as on the nuclear translocation and ubiquitination of phosphorylated Smad3, were examined. The interaction among Nedd4, PPARγ, and phosphorylated Smad3 was detected. In vivo, lathyrol ameliorated pathological fibrosis in the lungs of mice with pulmonary fibrosis and this effect was blocked by a PPARγ inhibitor. In vitro, lathyrol inhibited the transdifferentiation of fibroblasts into myofibroblasts, and these effects were suppressed by either inhibiting PPARγ activation or specifically silencing the PPARγ gene. Lathyrol inhibited the nuclear translocation of phosphorylated Smad3 and promoted its ubiquitination, while also enhancing the interaction among Nedd4, PPARγ, and phosphorylated Smad3. These effects were abolished following the specific silencing of either PPARγ or Nedd4. In conclusion, Lathyrol inhibits myofibroblast transformation by suppressing TGF-β/Smad pathway activation through PPARγ activation, thereby exerting its anti-pulmonary fibrosis effects. Full article

Atrial fibrillation (AF) is the most common sustained arrhythmia, and its initiation and progression involve multiple mechanisms, including electrical remodeling, structural remodeling, inflammatory responses, and oxidative stress. In recent years, the ubiquitin–proteasome system (UPS), a central pathway for maintaining intracellular protein homeostasis, has attracted increasing attention in the pathogenesis of AF. By regulating the degradation and expression of ion channel proteins, Ca²⁺-handling molecules, and pro-fibrotic signaling factors, the UPS plays a pivotal role in key pathological processes such as electrical and structural remodeling. Several E3 ubiquitin ligases (e.g., NEDD4-1/2, MuRF1, WWP1/2, TRAF6), deubiquitinating enzymes (e.g., JOSD2), and immunoproteasome subunits (e.g., β5i) have been shown to exert critical regulatory effects on atrial electrophysiological disturbances, interstitial remodeling, and inflammation. This review provides a comprehensive summary of the regulatory mechanisms of the UPS in AF-associated pathological processes, outlines potential therapeutic targets, and highlights current intervention strategies, including proteasome inhibitors, selective E3 ligase modulators, and natural compounds. Moreover, we discuss the latest advances and future perspectives regarding the application of UPS-based interventions in AF, aiming to provide theoretical foundations and research insights for the mechanistic exploration and innovative therapeutic development of AF. Full article

With the improvement of living standards, people’s awareness of health care is becoming stronger and stronger. Rabbit meat is a very high-quality and healthy meat, but its consumption is low due to its poor flavor. To explore the regulatory mechanism of nutrition on the meat quality of rabbits, twenty-four rabbits were fed a control diet or a high-fat (5 percent lard) diet over 15 days. The contents and tissues of the jejunum were subjected to 16S sequencing and mRNA transcriptome sequencing, respectively. The results indicated that there were significant differences in species diversity through beta diversity analysis (p < 0.05). The diversity of alpha in the experimental group was also significantly reduced (p < 0.05). Based on gene function annotation, 8 bacteria at the phylum level and 11 bacteria at the genus level that are related to the metabolism of adipose tissue showed significant differences between the two groups (p < 0.05). The transcriptome results of the jejunum showed significant differences in 135 genes between the experimental group and control group (p < 0.05). Gene annotation revealed 10 differentially expressed genes related to fat metabolism, which regulate 36 signaling pathways. We speculated that Alloprevotella may influence drip loss and cooked meat rate by changing the expression of PHGDH through correlation analysis. In addition, Coprococcus may influence IMF by changing the expression of NEDD4, ANGPTL3, and CYP8B1. These results indicated that a high-fat diet changed the species and composition of bacteria in the rabbit jejunum. Alloprevotella and Coprococcus may influence rabbit meat quality and flavor by changing PHGDH, NEDD4, ANGPTL3, and CYP8B1 gene expression in the host. This study laid a molecular foundation for the improvement of rabbit meat quality through nutritional diets. Full article

The allelopathic compound coumarin inhibits root growth across numerous species, but its mechanism is unknown. Through a genetic screen in Arabidopsis mutants, we identified the mutants for AXR1 (AUXIN RESISTANT 1) and ECR1 (E1 C-TERMINAL RELATED 1), two subunits of the NEDD8-activating enzyme (NAE), that are resistant to coumarin. Conversely, overexpression of the NEDD8-encoding gene RUB1 (RELATED TO UBIQUITIN 1) caused hypersensitivity, while the NAE inhibitor MLN4924 blocked coumarin’s effect. Since neddylation regulates auxin signaling, we analyzed downstream AUX/IAA proteins and found that the loss-of-function mutant of AUXIN RESISTANT 2 (AXR2) (also known as IAA7) was resistant to coumarin. We further showed that coumarin treatment leads to the accumulation of the AXR2 protein. Taken together, these results demonstrate that coumarin inhibits primary root growth by modulating auxin signaling via neddylation. Full article

Background: Gastric cancer (GC) remains a leading cause of cancer mortality. E3 ubiquitin ligases, as central regulators of protein stability and signaling within the ubiquitin–proteasome system, have been implicated in tumor progression, but their functional roles in GC are not well established. Methods: We integrated bioinformatics analysis of TCGA and GEO datasets, in vitro experiments (including cell proliferation, migration, and apoptosis assays), and computational modeling to identify key prognostic factors in GC. Results: We established two molecular subtypes (E3GC1/E3GC2) with distinct clinical outcomes and developed a 10-gene prognostic signature. The model showed moderate predictive accuracy (AUC: 0.61–0.71) and was validated externally. MMRN1 was upregulated in GC cells and its knockdown significantly inhibited malignant phenotypes. Critically, drug sensitivity analysis revealed high-risk patients were more sensitive to proteasome inhibitors (bortezomib), while low-risk patients responded better to taxane-based chemotherapy (docetaxel). Molecular docking predicted a high-confidence interaction between MMRN1 and NEDD4L, suggesting potential ubiquitination regulation. Conclusions: MMRN1 drives GC cell proliferation and migration in vitro and may be regulated by NEDD4L-mediated ubiquitination. Our study provides a foundation for E3 ligase-based patient stratification and personalized therapy selection in GC. While this study provides comprehensive multi-omics evidence supporting the role of MMRN1 in GC progression, its clinical translation is limited by the lack of in vivo validation and direct experimental evidence of NEDD4L-MMRN1 physical interaction. Further studies using animal models and clinical specimens are warranted to confirm these findings. Full article

To investigate the genetic regulatory mechanism of supplementary feeding on muscle development in Oula sheep, we employed transcriptomic analysis to explore the differentially expressed genes (DEGs) in the longissimus dorsi muscle of Oula sheep at different ages under conditions of supplementary feeding and non-supplementary feeding, as well as the significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways of DEGs. Moreover, by combining with the method of weighted gene co-expression network analysis, we screened for the potential hub genes that might play crucial roles. The results demonstrated that the CD4 and ICAM1 genes and the PI3K-Akt signaling pathway might exert important functions during the lamb stage. At the growth stage, the AGL, PGM2L1, PRKAA2, NEDD4, and GBE1 genes might serve as core genes to regulate the growth of skeletal muscle in Oula sheep after supplementary feeding through signaling pathways such as starch and sucrose metabolism and insulin signaling pathway. This outcome provides a molecular-level interpretation of the regulatory mechanism of supplementary feeding on muscle growth and development in Oula sheep at different ages, offering a theoretical basis for the further improvement of the meat quality of Oula sheep and the enhancement of the quality of livestock products in the Qinghai–Tibet Plateau region. Full article

Congenital ichthyoses, now grouped under the acronym EDD (Epidermal Differentiation Disorders), include nonsyndromic forms (nEDD) that may be caused by loss-of-function mutations in the CDSN gene encoding corneodesmosin (CDSN-nEDD, formerly Peeling skin syndrome type 1). It is characterized by skin peeling, inflammation, itching and food allergies, while no specific therapy is currently available. High levels of KLK5, the serine protease that initiates the desquamation cascade, are found in the epidermis of CDSN-nEDD patients. Thus, we hypothesized that KLK5 inhibition would alleviate the symptoms of CDSN-nEDD and could serve as a new pharmacological target. A human epidermal equivalent (HEE) model for CDSN-nEDD was developed using shRNA-mediated CDSN knockdown. This model was characterized and used to assess the role of KLK5 knockdown on CDSN-nEDD. Also, Klk5^−/− mice were crossed with Cdsn^epi−/− mice, the murine model of CDSN-nEDD, to examine in vivo the effect(s) of Klk5 deletion in CDSN-nEDD. Both models recapitulated the CDSN-nEDD desquamating phenotype. Elimination of KLK5 aggravated the CDSN-nEDD phenotype. Epidermal proteolysis was surprisingly elevated, while severe ultrastructural (corneo)desmosomal alterations increased epidermal barrier permeability and stratum corneum detachment was manifested. Based on these results, we concluded that targeting epidermal proteolysis with KLK5 ablation cannot compensate for the loss of corneodesmosin and rescue over-desquamation of the CDSN-nEDD. Possibly, in the absence of KLK5, other proteases take over which increases the severity of over-desquamation in CDSN-nEDD. The translational outcome is that over-desquamation may not always be rescued by eliminating epidermal proteolysis, but fine protease modulation is more likely required. Full article

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC. Full article

Introduction: NEDD8 Ultimate Buster 1 (NUB1) is a regulator of the cell cycle and a prognostic marker in cancer patients. However, its role in breast cancer (BC) and its response to 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) treatment remain unclear. This study investigated NUB1’s predictive value in FEC treatment and its mechanistic interaction with the oestrogen receptor (ER) in BC. Methods: MDA-MB-231 and MCF-7 cells were treated with FEC and analysed via flow cytometry for cell cycle distribution. Western blotting assessed NUB1 and ERα expression, while immunohistochemistry was conducted on a retrospective cohort (n = 85) from Malaysian hospitals to evaluate the clinical significance of NUB1 expression. Results: FEC treatment induced S and G2 phase cell cycle arrest in MDA-MB-231 cells (p = 0.04 and p = 0.02, respectively), accompanied by NUB1 upregulation. In MCF-7 cells, G2/M arrest was observed (p = 0.01), with reduced ERα expression and increased NUB1 levels in both cell lines. Lower cytoplasmic NUB1 expression was associated with poorer overall survival (OS) (HR = 0.60; 95% CI = 0.32–1.11; p = 0.10). Patients with low NUB1 and low ER expression showed the worst OS outcomes. Discussion: NUB1 upregulation following FEC treatment led to cell cycle arrest in ER-negative cells, whereas ERα suppression failed to induce S-phase arrest in ER-positive cells. Low NUB1 expression predicted poorer OS and increased BC recurrence. Conclusions: By integrating in vitro and clinical data, this study suggests that NUB1 may serve as a predictive biomarker in FEC-treated breast cancer. Larger studies are needed to validate and establish NUB1’s predictive role in FEC-treated patients. Full article

Speed and endurance are the primary goals in racehorse breeding. The Grassland-Thoroughbred is a newly developed breed in northern China that combines speed, endurance, and environmental adaptability. However, current research on the genetic background of this breed and the genes associated with athletic performance remains limited. We conducted whole-genome resequencing on Mongolian (MG), Thoroughbred (TB), Xilingol (XL), and Grassland-Thoroughbred (CY) horses, generating 3813.74 Gb of clean data after quality control. The number of transitions was significantly higher than that of transversions. The SNPs were mainly located in intergenic regions, followed by intronic regions. Principal component analysis, population structure analysis, and phylogenetic tree results indicated that the CYs had a distinct genetic background from MGs, TBs, and XLs, but based on PCA and phylogenetic clustering, they showed greater genetic similarity to Thoroughbreds. Using fixation index (Fst) and nucleotide diversity ratio (π ratio) analyses between CYs and the other three horse populations, 70, 76, and 80 candidate genes were identified from the intersection of the two methods, respectively. A total of 179 candidate genes were obtained from the union of the three groups. Candidate genes associated with athletic performance (ATF2, NDUFS7, PRKG1, IGFN1, MTOR, TTN) and growth and development (MTOR, IGFN1, COL21A1, NEDD4, PIEZO1) were screened. These genes are related to athletic ability and developmental processes in the CY population. Our study reveals genomic information associated with important traits in Grassland-Thoroughbreds and identifies valuable candidate genes, laying a foundation for future breeding and trait association studies. Full article

Lung cancer is the leading cause of cancer deaths among American men, even though various treatments are available. The discovery and use of new alternative drugs to treat lung cancers are needed to reduce lung cancer mortality. Phytochemicals are potentially desirable therapeutic agents due to their better safety profiles. Isorhapontigenin (ISO) is an orally bioavailable dietary stilbene. Our studies show that treatment with ISO inhibits human lung cancer cell growth, angiogenesis, invasion, and migration. Neural precursor cell expressed developmentally downregulated 9 (NEDD9), a multi-domain scaffolding protein, regulates various processes crucial for tumorigenesis and metastasis. Our results show that NEDD9 is upregulated in the lung tissues from human lung adenocarcinomas (LUADs) and squamous-cell carcinomas (LUSCs) compared to normal lungs. Overexpression of NEDD9 elevates the invasion and migration of human lung cancer cells. Treatment of human lung cancer cells with ISO decreases NEDD9 protein levels. Our studies have also demonstrated that NEDD9 positively regulates angiogenesis, an essential factor in cancer progression. ISO treatment reduces angiogenesis. Moreover, ISO reduces the protein levels of hypoxia-inducible factor-1α (HIF-1α), a transcription factor critical for angiogenesis. Aberrant high expression of β-Catenin leads to various diseases including cancer. Our results show that ISO treatment reduces the activation of β-Catenin through the downregulation of NEDD9. Studies indicate that ISO decreases NEDD9, causing the suppression of cell growth, angiogenesis, invasion, and migration of human lung cancer cells. ISO is a potent therapeutic agent for lung cancer treatment. Full article