Genes&Diseases

语种：英文出版周期：双月刊

E-ISSN：2352-3042P-ISSN：2352-4820

主管单位：重庆市教育委员会主办单位：重庆医科大学

Genes and Diseases是本由重庆医科大学于2014年创办的双月刊，也是国内第一本分子医学与转化医学相结合的全英文综合期刊，并入选“中国科技期刊卓越行动计划”高起点新刊项目。

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Cancer is a major cause of mortality globally, characterized by its multifactorial nature and intricate treatment procedures. The main treatment options include targeted drug therapies and chemotherapy. However, overcoming drug resistance remains a significant challenge in curing cancer patients. In recent decades, substantial efforts have been made to explore the resistance of cancer cells to anti-cancer agents and to create methods to counteract this resistance. Cancer cell resistance can be attributed to various factors, including long non-coding RNAs (lncRNAs) involved in cell cycle dysregulation, abnormal DNA repair, cell proliferation, epithelial–mesenchymal transition, metastasis, apoptosis, autophagy, drug efflux transporters, epigenetic modifications, and the formation of cancer stem cells. Pseudogenes are genomic regions that harbor impaired or dysfunctional versions of genes. Although pseudogenes were traditionally considered non-functional, a growing number of them are now being found to serve important biological functions. Recent research has demonstrated that mutations and dysregulation of pseudogene-derived lncRNAs are linked with various human diseases, such as cancer drug resistance. This review concentrates on exploring the latest discoveries that elucidate the diverse molecular functions of regulatory pseudogene-derived lncRNAs implicated in cancer drug resistance and the therapeutic possibilities for overcoming drug resistance.

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Cancer stem cells (CSCs), progenitor tumor cells with stemness characteristics, play key roles in cancer's onset, progression, metastasis, relapse, and chemotherapy resistance. While the exact molecular mechanisms of CSC development are not fully understood, recent research has revealed regulatory pathways of their generation with the weighty involvement of non-coding RNAs. It has been found that some pseudogenes are transcribed to long non-coding RNAs (lncRNAs), which are functionally and structurally similar to typical lncRNAs with biological functions including sponge miRNAs, antisense RNA, and interactions with proteins. Outstandingly, various in vitro and in vivo evidence have demonstrated that dysregulation of pseudogene-derived lncRNAs is directly involved in the development of CSCs in different cancers, mainly through functioning as miRNA sponges for modulating CSC-related signaling pathways. Therefore, researchers have suggested that research in this field can reveal hidden aspects of CSC development and can also open a new window for developing novel cancer therapeutic and diagnostic targets. In this review, we comprehensively address the recent findings of previous studies on the dysregulated roles of pseudogene-derived lncRNAs in directing and generating CSCs in various cancers. Also, their clinical capacities in terms of biomarkers, diagnosis, and treatment for cancer will be discussed.

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Oncolytic viruses (OVs) represent a cutting-edge approach to cancer immunotherapy, characterized by their ability to selectively infect and eliminate tumor cells while sparing healthy tissues. Among the diverse OVs, type 1 herpes simplex virus (HSV-1) stands out due to its robust oncolytic activity, genetic malleability, broad cell tropism, and well-documented clinical safety. Advances in genetic engineering have further amplified the therapeutic efficacy of HSV-1 by enhancing tumor specificity, replication efficiency, and immunogenicity. Clinically significant HSV-1-based oncolytic viruses, such as T-VEC and G47Δ, have gained regulatory approvals for treating melanoma and malignant glioma, respectively, highlighting their transformative potential in cancer therapy. The attenuation strategies employed in most oncolytic HSV-1 (oHSV-1) strains, while ensuring safety, often reduce viral replication and cytotoxicity. To address this limitation, retargeting strategies focusing on HSV-1 glycoproteins (gD, gH/gL, and gB) have been developed. These modifications aim to abolish canonical receptor interactions and achieve tumor-specific targeting through ligand-receptor binding. Recent breakthroughs in understanding HSV entry mechanisms have enabled the creation of fully retargeted HSV vectors with enhanced specificity and efficacy. This review explores the molecular mechanisms underlying HSV glycoprotein-mediated cell entry, examines recent advances in receptor-retargeted oHSV-1 engineering, and discusses the challenges and future directions in the development of oncolytic HSV-based therapies.

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Exosome-associated tRNA-derived fragments (tRFs) play crucial roles in cancer progression, influencing cell proliferation, metastasis, immune evasion, and drug resistance. Due to their stability and specific expression in bodily fluids, exosomal tRFs hold great promise as non-invasive biomarkers for early cancer diagnosis, treatment monitoring, and prognosis evaluation. Additionally, tRFs present opportunities as therapeutic targets, with potential to modulate oncogenic processes, such as controlling gene expression and modulating cellular signaling pathways. This review explores the diverse functions of exosome-associated tRFs in tumor biology, highlighting their potential for clinical applications, including their use as diagnostic tools and their role in therapy. It also addresses the challenges that remain in standardizing detection methods and validating their efficacy in clinical settings, such as variability in isolation techniques and the need for large-scale studies. Advanced technologies and further research will be key to unlocking their potential in personalized cancer therapy, ultimately aiming to integrate tRFs into routine clinical practice for better patient outcomes.

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Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a promising strategy to overcome resistance to chemotherapy. This review explores the mechanisms of ferroptosis and its potential to reverse drug resistance in digestive system cancers. We summarize recent advances in understanding the GPX4-regulated pathway, iron metabolism, and lipid peroxidation as key drivers of ferroptosis. It also highlights the roles of tumor heterogeneity, tumor–stroma interactions, abnormal apoptosis, metabolic alterations, and the tumor microenvironment in drug resistance. Specific mechanisms of ferroptosis resistance in esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, and colorectal cancer are discussed, along with strategies to induce ferroptosis to reverse drug resistance. Future research should focus on translating these findings into clinical applications through targeted therapies and combination treatments to improve patient outcomes.

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Vitamin C, also known as ascorbic acid, has sparked controversy since it first emerged as a potential anti-cancer agent. However, an increasing number of preclinical studies have demonstrated that high-dose vitamin C exhibits selective anti-tumor effects, including “pro-oxidative cytotoxicity”, “anti-cancer epigenetic regulation”, and “immune modulation”. Consequently, vitamin C has reemerged as a promising anti-cancer therapy in the form of high-dose administration. Advancements in pharmacokinetic research have facilitated the development of clinical trials. Early clinical studies across various cancer types have confirmed the safety of high-dose vitamin C administered via intravenous injection. Moreover, its use as an adjuvant therapy in combination with standard treatments, such as chemotherapy and radiotherapy, has shown promising therapeutic potential. However, there remains a lack of consensus regarding optimal dosage, administration methods, tumor specificity, and patient selection. These factors have contributed to the inconsistent outcomes observed in phase II clinical trials and have hindered the widespread conduct of phase III trials. Without robust clinical evidence, high-dose vitamin C, despite being a non-toxic and promising anti-cancer agent, risks being “shelved” once again. In this review, we provide a comprehensive overview of the anti-tumor mechanisms of high-dose vitamin C and a detailed analysis of preclinical and clinical studies investigating its role as an anti-cancer agent. Additionally, we explore emerging trends in high-dose vitamin C therapy for cancer treatment and offer recommendations for future research in this field.

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Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary renal disorder characterized by the progressive development of fluid-filled cysts within the kidneys, leading to renal dysfunction and potentially life-threatening complications. While ADPKD has long been considered a primarily genetic disorder, emerging evidence suggests that the immune microenvironment within the kidney plays a pivotal role in disease progression and severity. This review explored the intricate interplay between immune cells, inflammatory microenvironment, inflammatory pathways, complement system, and ADPKD, shedding light on the various immune components and mechanisms contributing to ADPKD pathogenesis. Key findings suggest that renal immune cell infiltration, inflammation, and the complement system could take part in cyst growth, renal fibrosis, and ADPKD progression. Inflammation, in particular, stands out as a prime candidate for therapeutic intervention. Moreover, recent studies have unveiled the involvement of immune checkpoints, such as PD-1 and its ligand PD-L1, in modulating the immune response within ADPKD kidneys. In conclusion, this review highlights the emerging paradigm shift in the understanding of ADPKD, emphasizing the pivotal role of the immune microenvironment in disease pathogenesis. Targeted therapies aimed at modulating immune responses and addressing immune-related checkpoints may hold promise for the development of novel treatments to improve the clinical outcomes of ADPKD patients.

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Leucine-rich repeat containing 8A (LRRC8A) is a member of the LRRC8 family, exhibiting broad expression across various tissues and cells in vertebrates. Like other LRRC8 family members, LRRC8A contributes to the formation of volume-regulated anion channels (VRACs), which are crucial for regulating cell volume and maintaining homeostasis. LRRC8A participates in diverse signaling pathways. Multiple studies have validated the links between LRRC8A dysregulation and neurological disorders, metabolic ailments, and tumors. This review provides a comprehensive overview of the regulatory mechanisms of LRRC8A in these pathologies. The primary goal was to assess the potential of LRRC8A as a therapeutic target for treating diseases and address key unresolved issues.

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Distraction osteogenesis, or the Illizarov technique, induces bone regeneration using distractive mechanical forces. Nevertheless, Wolff's law holds that bone adapts to reverse compressive mechanical loads, growing denser in areas of high pressure and resorbing in zones of low pressure. These two forms of new bone formation together suggest that mechanical stimuli play an important role in bone remodeling and regeneration. The therapeutic efficacy of distraction osteogenesis has been recognized in orthopedics and maxillofacial surgeries. Distraction osteogenesis was even used for the regeneration of various other tissues/organs, such as blood vessels and skin (e.g., in the treatment of limb ischemic diseases and foot ulcers), suggesting the principle of distraction histogenesis. However, the underlying mechanisms, particularly those of the cross-organ effects and in terms of mechanotransduction, remain poorly understood. Thus, this review aims to explore the recent advances in research on musculoskeletal regeneration and its association with mechanosensitive channels from a new interdisciplinary application perspective. The contents can provide insights into potential research directions for understanding the molecular mechanisms of musculoskeletal regeneration and its clinical applications.

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The regulation of gene expression is pivotal in cancer development, with increasing emphasis on epigenetic modifications such as RNA methylation. N6-methyladenosine (m6A), the most abundant RNA modification, critically impacts RNA function and stability. METTL16, an m6A methyltransferase or “writer”, is essential in this modification process. Aberrant expression of METTL16 is closely linked to cancer cell proliferation, invasion, metastasis, and drug resistance, through modulation of RNA metabolism. Despite extensive research on RNA-modifying enzymes, the specific mechanisms and roles of METTL16 in cancer remain poorly understood. This review provides a detailed examination of METTL16's functions and regulatory mechanisms in cancer, emphasizing its m6A-dependent and m6A-independent roles in regulating RNA stability and function. Furthermore, it proposes that targeting METTL16 represents a promising avenue for cancer therapy.

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T-box transcription factor 4 (TBX4), a crucial member of the T-box gene family, is essential for embryonic development, particularly in the formation of hindlimbs and lungs. Beyond these developmental roles, TBX4 is integral for maintaining the structural integrity and function of the respiratory, motor, and nervous systems. Dysregulation of TBX4 is implicated in serious diseases, including pulmonary hypertension, small patella syndrome, and tracheal stenosis, with mutations and aberrant expression patterns emerging as potential diagnostic markers. Additionally, TBX4 contributes to tumorigenesis in cancers such as pancreatic, lung, and bladder cancers, where recent studies suggest DNA methylation as a primary mechanism underlying TBX4 suppression, positioning it as a promising prognostic marker. Despite these advances, the precise functions and regulatory mechanisms of TBX4 remain insufficiently understood. This review consolidates current knowledge on the roles and molecular mechanisms of TBX4 in mammalian embryonic development and its association with diseases, highlighting the need for further research into its contributions to human health.

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Recent advances in gene editing using the CRISPR/Cas system have revolutionized genome editing, opening new horizons for human cellular and gene therapy products. Genome editing technologies are rapidly being adopted in clinical trials. However, critical non-clinical safety considerations are required to address challenges in translating research to the clinic. Here, we review current ex vivo and in vivo genome editing approaches using the CRISPR/Cas system and discuss the practical use of these methods in pre-clinical studies and in the clinic. We also discuss known limitations of genome editing in humans and the mitigation of risk factors associated with it from a non-clinical safety perspective. This review aims to aid researchers in acquiring a perspective that is essential for the safe translation of genome editing to the clinic.

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Over the last few decades, platinum-based chemotherapy has served as the standard chemotherapy in treating ovarian cancer (OC). While most patients initially respond well to platinum-based chemotherapy, approximately 70% of patients eventually relapse and confer resistance to platinum. Recent preclinical evidence on platinum-resistant ovarian cancer (PROC) is encouraging. Various potential mechanisms, such as genomic and epigenetic alterations, pharmacological alterations, DNA damage repair, metabolic reprogramming, the tumor microenvironment (TME) and programmed cell death, have been implicated in platinum resistance. In addition, clinical trials regarding the treatment of PROC have shown considerable success, and a multitude of promising therapies are in progress. In this review, we comprehensively summarized the underlying mechanisms of platinum resistance in OC and proposed the most promising novel therapeutics and strategies employed in the treatment of PROC.

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Intestinal macrophages are critical regulators of mucosal immunity, playing essential roles in microbial surveillance, barrier maintenance, and tissue repair. As highly responsive immune cells, they integrate diverse environmental cues to dynamically adapt to their functional states. In recent years, RNA modifications have emerged as a key layer of post-transcriptional regulation, orchestrating macrophage development, polarization, and immunometabolic programming. This review focuses on the role of epitranscriptomic regulation in shaping the plasticity of intestinal macrophages, systematically summarizing how RNA modifications influence their responses to inflammatory stimuli, microbial signals, and intercellular communication. We further highlight the regulatory potential of RNA modifications in gut immune homeostasis and inflammatory diseases, providing a comprehensive framework for understanding RNA-mediated immune regulation and a forward-looking perspective on targeting these pathways in intestinal disorders.

179

Esophageal squamous cell carcinoma (ESCC) ranks among the top six deadliest malignancies globally, characterized by an alarmingly low five-year survival rate. This aggressive cancer is especially prevalent in Asian countries, where it is strongly influenced by various factors, including dietary habits. Organoids, a novel bioresource that are three-dimensional, miniature organ-like structures derived from stem cells or cancer cells in a laboratory, closely mimics the architecture and function of actual organs, providing an enhanced model for in vivo disease representation. These structures hold immense promise for advancing disease modelling, drug testing, personalized medicine, and investigating intricate biological processes. Nevertheless, numerous challenges remain, warranting further investigation. This review offers insights into the superiority of organoids in ESCC disease modelling, especially in drug screening and treatment optimization. The combination of organoids with gene editing will elucidate mechanisms of ESCC, which will be helpful for early molecular marker discovery and immunotherapy, providing potential strategies for therapeutic targets and personalized intervention.

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Parkinson's disease (PD) is a complex neurodegenerative disorder that poses significant burden on patients and families. Its exact cause is unknown, resulting in limited effective treatments. Mitochondrial dysfunction, linked to genetics, aging, oxidative stress, and environmental factors, is central to PD. Healthy elderly individuals have a compensatory mitochondrial DNA (mtDNA) mechanism in brain cells, but this mechanism is impaired in PD patients, leading to mtDNA reduction, respiratory chain dysfunction, decreased adenosine triphosphate (ATP) synthesis, and inadequate neuron energy. Aging increases oxidative stress, impairing mitochondrial function. Mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra causes neuronal loss and disease progression. Aging microglia also play a crucial role, with a reduced capacity to clear neurotoxic substances, especially in the substantia nigra. A decrease in triggering receptor expressed on myeloid cells 2 (TREM2) gene expression shifts microglia to a pro-inflammatory phenotype, exacerbating neuroinflammatory responses and protein deposition. Down-regulation of the C-X3-C motif chemokine ligand 1 (CX3CL1)/C-X3-C chemokine receptor 1 (CX3CR1) signaling pathway increases the expression of pro-inflammatory cytokines, accelerating neuronal loss and disease progression. Recent research has identified a new astrocyte aging regulatory mechanism involving the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, promoting astrocyte aging and exacerbating dopamine neuronal loss and motor dysfunction. Understanding PD pathogenesis, especially mitochondrial dysfunction, aging, and glial cell changes, is crucial for developing effective treatments.

175

SARS-CoV-2 has evolved dramatically since the COVID-19 pandemic in Dec 2019, acquiring mutations that enhance transmissibility, infectivity, and immune evasion.1 Unlike other variants targeting lungs, Omicron altered entry pathways and promoted replication in the upper respiratory tract, resulting in more asymptomatic cases. This facilitated its spread and posed challenges to infection prevention.2 Healthcare workers face a higher risk of being infected and should seek to protect themselves from virus transmission while providing medical care for patients.3 Passive antibody therapy based on neutralizing antibodies has been found to protect susceptible populations with moderate to severe immunodeficiency or vaccine contraindications. Antibodies MY-586 and MY-558, obtained from recovered patients of SARS-CoV-2 infection, have shown strong neutralizing efficacy against various mutant strains of SARS-CoV-2.4 Preclinical toxicity studies in mice, monkeys, and healthy volunteers revealed that A8G6, the intranasal spray formulated with MY-558 and MY-586 at a mass ratio of 4:1, had high tolerance and no serious side effects. It has been confirmed to have potent efficacy in preventing SARS-CoV-2 infection in close contact with COVID-19 patients.5 Our study aimed to evaluate the efficacy and safety of A8G6 in safeguarding healthcare workers in field hospitals.

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Immune checkpoints (ICPs) are immunologically functional membrane proteins essential for maintaining self-tolerance and regulating immune responses to prevent tissue damage.1 These molecules function through receptor–ligand interactions between T cells and antigen-presenting cells, balancing co-stimulatory and co-inhibitory signals. While therapies targeting ICP, such as inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cluster of differentiation 80 (CD80)/CD86/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have transformed cancer treatment, increasing evidence suggests that ICPs are also involved in the pathogenesis of cardiovascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerosis.2 Notably, ICP receptors and ligands exhibit context-dependent roles in cardiovascular diseases, with diverse expression patterns and functions.3 Building upon our previous findings, identifying T cell-mediated vascular inflammation, including responses from CD4+ Foxp3+ regulatory T cells (Tregs), plays a critical role in AAA and atherosclerosis, we aimed to comprehensively characterize the ICP landscape in these conditions. To achieve this, we integrated Omics data with quantitative reverse transcription PCR validation to profile 58 receptor–ligand pairs (86 genes) across both murine and human datasets (Table S1). In our analysis of 10 AAA transcriptomic datasets (Fig. 1A), we observed consistent up-regulation of the inhibitory pairs CD47/signal regulatory protein alpha (Sirpa) and selectin P ligand (Selplg)/V-set immunoregulatory receptor (Vsir), as well as the stimulatory pair TNF superfamily member 14 (Tnfsf14)/TNF receptor superfamily member 14 (Tnfrsf14), particularly at early disease stages (Day 7 of angiotensin II infusion) compared with Day 28 in apolipoprotein E deficient (ApoE−/−) aortas. Notably, expression patterns were gender-specific; the CD47/Sirpa pair was up-regulated in females, while only Sirpa was increased in males. Selplg was up-regulated in both sexes, but Vsir remained unchanged, highlighting the complexity of immune modulation in AAA in a gender-dependent manner. These findings suggest that both co-stimulatory and co-inhibitory ICPs are inducible during AAA and may help maintain immune homeostasis and limit disease progression, especially during early stages.

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Breast cancer (BC), the most prevalent cancer type in women worldwide, exhibits significant heterogeneity across individual cases. The existing subtyping schemes for BC are all based on the expression of a few marker genes or proteins, which could not well capture samples sharing common or similar biology, which has substantially limited their applications.1 We present a new classification scheme for BC samples based on predominantly co-expression patterns of metabolic genes at the genome scale using a suite of machine-learning methods, resulting in four classes. Our consideration is: i) Extensive metabolic reprogramming is observed in cancer and considered as a hallmark of cancer2; and ii) all abnormal behaviors exhibited by cancer tissue cells are the direct results of these reprogrammed metabolisms, which are induced to adapt to specific stressors in the cancer-promoting microenvironments.3 In addition, the classification of BC tissues based on genome-scale metabolic genes expressions can ensure the stability of the classification results. Compared with the current PAM50-based BC subtypes, samples in each of our four classes have more outstanding shared metabolic characteristics, clinical features, genomic alterations, tumor microenvironments, immune-cell infiltrations, immunotherapy responses, and chemotherapy sensitivities, making our classification results more informative and potentially more useful.

168

Alagille syndrome (ALGS) is a rare, autosomal dominant disorder that affects multiple systems. It was first reported by Alagille et al in 1969 and further elaborated on its clinical, biochemical, and histological features in 1975. The main organs involved in the disease include the liver, heart, eyes, bones, and kidneys. As a rare genetic disease, ALGS is primarily observed in children, and confirmed cases in adults are rarely reported. Therefore, we report a case of an adult female who has been diagnosed with ALGS, and the genetic testing revealed a heterozygous mutation at position 933_934 of the Jagged 1 (JAG1) gene, which was discovered for the first time.

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Human renal cell carcinoma ranks among the most prevalent forms of cancer.1 The predominant subtype, clear cell renal cell carcinoma (ccRCC), constitutes approximately 80% of all kidney cancer cases.2 The collagen triple helix repeat containing-1 (CTHRC1) gene encodes an extracellular matrix-associated protein that is up-regulated in various human tumors and is intricately linked to cellular processes such as proliferation, invasion, and metastasis.3,4 It has been demonstrated that CTHRC1 facilitates tumor initiation and progression by modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, thereby enhancing tumor dissemination, invasion, migration, adhesion, and metastasis.5 In this study, a multilevel analysis was launched to deeply investigate the role of CTHRC1 in patients with ccRCC by bioinformatics, and as a supplement to it, in vitro and in vivo experiments were performed to disclose the biological effects of CTHRC1 and explore its therapeutic value. This study demonstrates that CTHRC1 promotes ccRCC progression via the PI3K/AKT/glycogen synthase kinase 3 beta (GSK3β) signaling pathway.

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Hearing loss is a common health condition associated with genetic variations, diseases, loud noise exposure, and aging. Diabetes mellitus, one of the most prevalent chronic diseases, is known to increase the incidence of hearing loss in humans. However, no effective therapeutics have been developed to treat diabetes-related hearing loss (DRHL). The most evident histopathologic characteristic in the cochleae of diabetic patients is degeneration of the stria vascularis and cochlear outer hair cells (OHCs).1 For noise-induced hearing loss (NIHL), damage to hair cells is also a principal cause.2 Therefore, promoting hair cell survival would be critical for preventing DRHL and NIHL.

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Phenylketonuria (PKU), one of the most common genetic metabolic disorders, is due to defective activity of phenylalanine hydroxylase (PAH), a member of the aromatic amino acid hydroxylases. In PKU patients, phenylalanine (Phe) levels in the blood and brain increase with clinical manifestations of severe intellectual disability and some other abnormalities. The exact mechanism and impacting factors of PKU are not completely elucidated. The therapy for PKU is mainly through a Phe-restricted diet to limit the uptake of Phe. In addition, tetrahydrobiopterin serves as an adjuvant pharmacologic therapy, primarily by its possible activity-boosting effect as a cofactor for PAH. Besides tetrahydrobiopterin, it is known that PAH additionally requires Fe2+ and O2 as cofactors (Fig. 1A). In this work, we generated a D. melanogaster PKU model to explore its regulatory mechanism. We found that the Phe-sensitivity of PKU Drosophila was strongly modulated by iron, and the eclosion defect could be almost completely rescued by tyrosine and L-3,4-dihydroxyphenylalanine (l-DOPA). The effect of iron on PKU was further confirmed in mouse PKU models.

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Obesity-related metabolism diseases, such as obesity, insulin resistance, hyperglycemia and hyperlipemia, have emerged as important chronic disease.1,2 BCI hydrochloride (BCI), a small-molecule inhibitor that reportedly can effective to decrease the dual-specificity phosphatases (DUSP) 1 and 6 phosphatase activity,3 is linked to several biological processes, such as preventing tumor development and macrophage inflammation.4,5 This study was performed to investigate the role and mechanism of BCI treatment on glucose and lipid metabolism in mice. Results showed that BCI markedly reduced epididymal adipose tissue weight in diet-induced obese (DIO) mice. In addition, BCI-treated obese mice showed better glucose clearance and less hyperglycemia than control mice. Furthermore, the gene expression of lipolytic genes in the epididymal adipose tissue were higher in BCI treatment mice than those in control mice.

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Silicosis is caused by long-term inhalation of large quantities of free silica dust and is characterized by pulmonary dysfunction, persistent inflammation of the lungs, formation of silicosis nodules and irreversible pulmonary fibrosis, leading to respiratory failure and eventual death. Pulmonary macrophages, as the first line of defense of the lungs, engulf and remove inhaled silica dust particles.1 Long-term exposure to silica dust can cause macrophages to be damaged, release various cytokines and chemokines, and induce inflammatory responses.2 Macrophages also activate fibroblasts during the inflammatory process, leading to the formation of fibrosis. They further exacerbate fibrosis in the lungs by secreting pro-fibrotic factors such as TGF-β, which promotes the accumulation of collagen and other extracellular matrix components.3 Fra-2 is a transcription factor (TF) in the AP-1 family that has received relatively little attention. Previous studies have confirmed that Fra-2 expression is up-regulated in IPF lung tissue, and Fra-2 transgenic mice exhibit spontaneous pulmonary fibrosis.4 TGF-β1 is a potent fibrogenic factor that plays important regulatory roles in fibrotic diseases, including cell proliferation, differentiation, migration, immunomodulation, and extracellular matrix (ECM) transformation, and is involved in tissue repair and fibrosis. Sashwati Roy et al found that deletion of the AP-1 binding site resulted in higher basal TGF-β reporter activity under 5% O2 conditions, suggesting that TGF-β expression was derepressed in the absence of AP-1 binding.5 These studies suggest a close interaction between Fra-2 and TGF-β1 signaling pathways. We speculate that Fra2 may promote pulmonary fibrosis in silicosis mice by controlling the release of TGF-β1 from macrophages.

159

Liver cancer is the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) constitutes about 90% of liver cancer cases. Most HCC patients are not diagnosed until the disease has progressed to intermediate or advanced stages, rendering effective treatments unfeasible.1 Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage HCC. However, approximately 50% of patients develop resistance to TACE, presenting a significant clinical challenge.2 Oxaliplatin (OXA), commonly used in TACE, primarily exerts its cytotoxic effects through nucleolar stress pathways.3 However, resistance to OXA often develops. Although several resistance mechanisms, including the prostate cancer gene expression marker 1 (PCGEM1)/miR-129-5p/ETS variant 1 (ETV1) and lysine-specific demethylase 1 (LSD1)/long intergenic non-protein coding RNA 1134 (LINC01134)/specificity protein 1 (SP1)/p62 pathways, have been identified recently, most investigations have been limited to in vitro studies. Here, we report glutamate-rich WD repeat containing 1 (GRWD1) as a novel mediator of TACE resistance in HCC. Mechanistically, GRWD1 reduces OXA sensitivity by competing with mouse double minute 2 (MDM2) for nucleophosmin 1 (NPM1) binding, thereby disrupting NPM1-mediated p53 stabilization and inhibiting nucleolar stress responses. Furthermore, GRWD1 expression correlates with TNM staging and shows promise as an independent prognostic biomarker for HCC. These findings provide new insights into both the diagnosis and treatment of HCC.

162

The plasticity of cancer cells enables them to adapt to selective pressures, further enhancing their survival advantage and resistance to apoptosis. Cancer cell plasticity operates through multiple mechanisms. Among them, the key to successful cancer metastasis mainly depends on epithelial–mesenchymal transition (EMT) and anoikis resistance. EMT enables cancer cells to acquire migratory and invasive capabilities, allowing them to overcome tissue barriers and adapt to new environments.1 Anoikis resistance enables detached cancer cells to circumvent the apoptotic response that occurs upon detachment from their normal extracellular matrix environment.2 Hematological and neurological expressed 1 (HN1) has been shown to influence integrin-mediated cell adhesion and signaling, critical for cell-extracellular matrix interactions and anchorage-dependent cell survival.3 HN1 can determine the survival of cancer cells under conditions of extracellular matrix adhesion changes through integrins. These effects further validate the importance of HN1 in the regulation of cancer cell survival and metastasis. Though HN1 acts as an EMT regulator or mediator for downstream signaling pathways in different cancers, the role of HN1 in anoikis resistance has not been reported before.

171

Ischemic stroke is a severe neurological condition and a leading cause of disability and death worldwide.1 It occurs when blood flow to the brain is critically reduced, depriving cells of oxygen and glucose, which leads to significant cell damage and death. Developing effective therapies for ischemic stroke requires a precise understanding of the downstream mechanisms of Notch intracellular domain 1 (NICD1), which plays a pivotal role in stroke pathology. However, these mechanisms remain only partially understood. Clarifying NICD1 pathways could not only provide promising strategies for stroke therapy but also reveal innovative targets for broader neuroprotective interventions.

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Nephronophthisis (NPH), an autosomal recessive tubulo-interstitial nephropathy, is characterized by interstitial inflammation and progressive kidney fibrosis. To date, mutations in more than 25 NPHP genes have been associated with NPH, resulting in a wide genetic heterogeneity and overlapping clinical phenotypes. However, 53% of the patients with a genetic diagnosis have biallelic mutations in NPHP1.1 Fibrosis is caused by excessive matrix deposition, mainly by activated myofibroblasts. Inflammatory signals play a central role in the differentiation and expansion of myofibroblasts. The interleukin 1 (IL1) family of cytokines is one of the most potent triggers of innate immune response. The activity of IL1 is mediated by its type I receptor (IL1R) whose intracellular domain shares similarities with the Toll protein in fruit flies, known as the Toll interleukin-1 receptor (TIR) domain. When the cytokine binds, IL1R initiates a signaling cascade through recruiting cytoplasmic myeloid differentiation primary response protein 88 (MYD88), IL1R associated kinase 4 (IRAK4) and tumor necrosis factor receptor-associated factor 6 (TRAF6) resulting in the activation of the NFκB pathway, among others. In the kidney, in vitro studies reported that both IL1α and IL1β promote TGF-β production and fibronectin production in human proximal tubular cells. IL1β also promoted the conversion of kidney tubular epithelial cells into myofibroblasts, the primary drivers of collagen deposition.2 This finding was also supported by another study where treatment with IL1β triggered myofibroblast activation, matrix production, collagen deposition and fibrosis in kidney organoids.3

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Hirschsprung disease (HSCR) is a congenital intestinal motility disorder characterized by absent enteric ganglia in the distal intestine.1 While HSCR is primarily a genetic disorder, its inheritance pattern is complex and remains largely unexplored.2 Current genetic screening focuses on rare variants of several essential genes (e.g., RET, EDNRB, GDNF, SOX10), which unfortunately could explain only a limited portion of genetic heritability.3 The interplay between common and rare variants may significantly impact disease risk.4 Endothelin receptor type B (EDNRB) is a well-established HSCR contributor5 and was previously considered to explain about 5%–10% of HSCR children. While rare coding EDNRB variants are associated with HSCR, the contribution of common variants and their interaction with rare variants remains unclear. To address this, we conducted a large-scale genetic study involving 553 HSCR participants and 2075 controls from southern Chinese children, employing single nucleotide polymorphism (SNP)-array genotyping, exome sequencing, and genome sequencing (Fig. 1A). Our study aims to elucidate the role of EDNRB in HSCR susceptibility, explore the interplay between common and rare variants, and provide mechanistic insights into HSCR pathogenesis through functional studies.

162

The connexin family of mammalian gap junction proteins provides intercellular communication channels critical for development and tissue function. Mutations in connexins are associated with numerous diseases including deafness, skin diseases, cataracts, cardiac diseases, neurological diseases, cancer, and complex syndromic disorders. Connexin 43 (Cx43, encoded by GJA1) is the most widely expressed and studied member. We and others have shown that, through a poorly understood mechanism of direct internal translation initiation, the single coding exon of GJA1 generates various N-terminally truncated Cx43 forms, notably the 20 kDa (k) form GJA1-20k.1,2 Numerous functions have subsequently been ascribed to these truncated forms, providing critical insight into non-canonical GJA1 functions.3

165

Early detection and effective treatment, as well as prevention of recurrence and metastasis, are crucial for patients with non-small cell lung cancer (NSCLC).1 Recent studies have shown that alkylation repair homolog 5 (ALKBH5) reverses m6A RNA methylation. Silencing ALKBH5 affects tumorigenesis and cancer progression under the action of m6A reading proteins, such as YTH domain family 3 (YTHDF3).2 The Yes-associated protein (YAP) pathway regulates cell proliferation, apoptosis, invasion, migration, and epithelial–mesenchymal transition (EMT),3 all processes that play a key role in tumor growth and metastasis.4 One notable EMT-related protein is zinc finger E-box–binding homeobox 1 (ZEB1), implicated in tumor progression.5 Currently, few studies have investigated the functions of these tumorigenic proteins in NSCLC. Here, our research revealed that ALKBH5, YTHDF3, YAP, and ZEB1 constitute the cellular axis regulating NSCLC cell proliferation, migration, invasion, and EMT in an m6A-dependent manner. Methylation inhibitor cycloleucine blocked this axis. Based on our findings, we propose that ALKBH5 plays an important supportive role in NSCLC tumor growth and metastasis. Thus, ALKBH5-mediated inhibition of YAP m6A modification is a promising novel target for NSCLC therapy.

169

Environmental carcinogens from air pollution and metal exposure have emerged as major sources for inducing cancers. Epidemiological data have shown that hexavalent chromium (Cr [VI]) is linked to cancer development. A list of evidence supports the association between occupational exposure to hexavalent chromium and various cancers, especially lung cancer.1 However, the underlying mechanisms by which Cr (VI) induces cancers are still unclear. As the most prevalent mRNA modification, N6-methyladenosine (m6A) provided a novel form of post-transcriptional gene regulation. m6A regulators were found to be closely correlated with specific malignant tumors, including lung cancer. Among these, METTL3, the core methyltransferase for m6A modification, has gradually attracted much attention due to its cancer-promoting role in multiple cancers.2 However, the exact roles of METTL3 and m6A methylation in carcinogenesis induced by chronic chromium exposure and lung cancer development remain unclear.

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Pheochromocytomas and paragangliomas (together PPGLs) are rare neuroendocrine tumors arising from chromaffin cells located in the adrenal medulla and ganglia of the autonomic nervous system, respectively. Although paragangliomas located in the head and neck region (HNPGLs) represent approximately 60% of all paragangliomas,1 their genetic basis remains less well understood than that of PPGLs with other locations. Furthermore, HNPGLs have been largely excluded from comprehensive genomic profiling studies, leading to the classification of PPGLs into three molecular clusters: pseudohypoxic (C1), kinase signaling (C2), and Wnt-altered (C3). As a result, our understanding of the molecular basis of these tumors is limited, and the discovery of genes exclusively mutated in HNPGLs, such as DNA methyltransferase 3 alpha (DNMT3A),2 suggests that unique molecular pathways could be involved in their development. Here, we performed a multi-omic characterization of wild-type (WT) HNPGLs, which revealed the existence of two molecular subgroups: succinate dehydrogenase (SDH)-like and DNMT3A-like. In SDH-like HNPGLs, we identified previously undetected alterations in SDH genes despite their positive SDHB immunohistochemistry (IHC), highlighting the risk of overreliance on this method for genetic diagnosis of HNPGLs.3 Tumors within the DNMT3A-like cluster showed molecular characteristics consistent with polycomb repressive complex 2 (PRC2) dysfunctions, and stromal antigen 2 (STAG2) emerged as a promising new driver.

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Tumor cells undergo metabolic reprogramming to enhance biomass uptake, which is crucial for their survival and proliferation.1,2 Lactate, traditionally considered as an energy substrate, promotes tumor growth by inducing histone lactylation, which alters gene expression and chromatin structure.3 This lactylation process influences tumor progression through immunosuppression, metabolic reprogramming, and macrophage polarization.4,5 However, how lactylation drives cancer development remains unclear. This study explores lactylation in tumor progression across 32 cancer types. A pan-cancer prognostic model based on lactylation-related genes (LRGs) was constructed using TCGA RNA transcriptome data. Cox, Lasso regression, and Kaplan–Meier survival analysis were employed to establish a survival prognostic score (Lscore). High lactylation levels were linked to poor patient prognosis, through influencing immune cell infiltration and promoting tumor metastasis by accelerating the cell cycle. Single-cell RNA sequencing revealed that lactylated cells were predominant in advanced tumor stages, with pathway analysis suggesting connections between lactylation, metastasis, immune cell phagocytosis, and lipid metabolism. This research deepens our understanding of tumor biology through lactylation, offering valuable insights for the development of novel therapeutic strategies and personalized treatment approaches. The workflow for constructing the LRGs signature of pan-cancer is depicted in Figure 1A.

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuronal loss, mitochondrial dysfunction, and neuroinflammation.1 Hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) contributes to PD pathology by depleting nicotinamide adenine dinucleotide (NAD+) and promoting cell death. While PARP1 inhibitors like PJ34 can attenuate neurodegeneration, their efficacy may be limited when used alone.2 NAD+ supplementation has shown promise in maintaining mitochondrial integrity and reducing inflammation, but has not been extensively combined with PARP1 inhibition.3 This study explores the therapeutic synergy of co-administering NAD+ and PJ34 in a 6-hydroxydopamine (6-OHDA)-induced PD model.4 We demonstrate that this combination enhances neuronal survival, suppresses neuroinflammation, and promotes autophagic flux more effectively than monotherapies, providing a compelling strategy to concurrently target energy metabolism and DNA repair pathways.

161

G protein subunit alpha O1 (GNAO1)-related disorders (GNAO1-RD) are a group of ultra-rare neurological conditions characterized by a wide spectrum of clinical features, including movement disorders, developmental delay or intellectual disability, epilepsy, and feeding difficulties. The severity of these conditions can range from mild to severe,1,2 with life-threatening episodes of dyskinetic crisis being a hallmark of the disorder in many cases.3 The Gαo protein, encoded by the GNAO1 gene, is a crucial component of G protein-coupled receptor (GPCR) signaling. It mediates interactions between receptors and intracellular effectors, playing an essential role in neuronal communication and regulation. Structurally, Gαo consists of a Ras-like domain (RHD) and an α-helical domain (AHD), which coordinate nucleotide binding and signaling, along with an N-terminal α-helix (αN). While mutations in the RHD are well-studied due to their role in enzymatic activity and interactions, the functional impact of mutations in the AHD, such as the novel N76K variant of GNAO1, is less understood. Here, we report and analyze the N76K variant, focusing on its effects on Gαo activity and signaling pathways.

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Inactivated phosphoinositide 3-kinase gamma (PI3Kγ) syndrome (IPGS; OMIM #619802), an autosomal recessive immunologic disorder first described by Takeda et al in 2019, classically manifests in childhood with recurrent infections, pneumonia, and colitis.1 This disorder is caused by biallelic loss-of-function variants in the PIK3CG (OMIM ∗601,232), located at 7q22.3, encoding the catalytic subunit p110γ of the PI3Kγ enzyme. The p110γ subunit, predominately expressed in immune cells and responsible for chemotaxis, reactive oxygen species (ROS) generation, and cytokine generation, also maintains critical roles in endothelial cells, neurons, cardiomyocytes, and lung cells.2,3 Pathogenic variants in PIK3CG disrupt PI3K signaling, leading to immune dysregulation characterized by antibody deficiency, excessive T cell infiltration in the lungs/intestines, and significantly disrupted levels of T regulatory cells.1,4

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Aging is a natural process characterized by the progressive decline in tissue and cellular functions, while recent studies indicated the potential reversibility of aging. Gene reprogramming is a typical method that involves cellular reprogramming. The Yamanaka factors, comprising Oct4, Sox2, Klf4, and c-Myc (termed OSKM), have been shown to convert senescent cells into induced pluripotent stem cells and mitigate signs of premature aging in presenile mice. Despite these promising results, the continuous expression of Yamanaka factors induces teratomas and severe mortality, primarily due to the oncogenic properties of c-Myc. It is well-established that c-Myc functions as a key transcription factor for activating the telomerase gene (TERT), and the absence of c-Myc may impede telomere elongation, thereby compromising anti-aging effects. To address these issues, this study employed an optimized Yamanaka factor (Oct4-Sox2-Klf4, OSK) that excludes c-Myc in conjunction with TERT gene therapy. Through a series of experimental validations, we confirmed that the co-expression of the OSK and TERT genes significantly enhanced the expression of genes associated with youth while concurrently reducing the levels of senescence-associated genes. Consequently, this combined gene therapy represents a promising therapeutic strategy for extending lifespan and addressing aging-related diseases.

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The CRISPR-Cas system is a powerful genetic engineering tool and can be conveniently used for the generation of diverse gene-knockout models. One CRISPR-Cas system, CRISPR-Cpf1 (also known as Cas12a), recognizes the AT-rich protospacer-adjacent motif (PAM) present at the 5′ end of the target sequence and requires CRISPR RNA (crRNA), but not transactivating crRNA (tracrRNA) for its activity.1 Unlike Cas9, Cpf1 can produce multiple mature crRNAs by processing a concatemeric crRNA precursor and thus is useful for the multiplex gene targeting.2

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Brenner tumors are a relatively rare type of epithelial ovarian tumor, and while most Brenner tumors are benign, malignant Brenner tumors (MBT) account for about 1% of cases,1 and their tumor microenvironment remains largely unexplored. In this study, a 68-year-old woman was diagnosed with MBT based on the following pathologic findings: molecular pathology was positive for P67 and cytokeratin 7 (CK7) and negative for cytokeratin 20 (CK20), uroplakin, and P16. Single-cell sequencing was used to analyze cell heterogeneity in this rare case of early MBT and in two cases of early high-grade serous ovarian cancer (HGSOC). Six different cell types in the MBT tumor microenvironment were identified. Compared with HGSOC, the proportion of MBT immune cells was significantly reduced. Increased proportions of the Macrophages_1 subgroup and Fibroblasts_RGS5 subgroup further led to immunosuppression. The interaction of MBT cells with tumor infiltrating immune cells through co-stimulatory signaling, chemokine interactions, and immune checkpoint pathways enhanced the immunosuppressive tumor microenvironment.

169

Aberrant accumulation of myeloid stem cell precursors within the bone marrow caused acute myeloid leukemia (AML), leading to a disruption of normal hematopoiesis. Despite significant therapeutic advancements improving AML patient outcomes, up to 70% of individuals aged 65 or older succumb within the first year of diagnosis.1 Identifying new targets for AML treatment remains important. SRSF7, an important member of the family of serine/arginine-rich splicing factors (SRSFs), was characterized as a key regulator of mRNA export.2 A wealth of research has highlighted multifaceted contributions of SRSF7 to oncogenic mechanisms, but its role in AML progression is yet to be investigated.

165

The GGGGCC repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) is a leading genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Despite the prevalence of this mutation, effective therapies remain elusive due to the complexity of the disease. Our study leverages Drosophila models to investigate the role of surface glia in mediating the toxicity associated with mutant C9orf72. With widely used neuronal and glial GAL4 (galectin 4) drivers and recently developed GAL4 drivers that separately mark each subtype of the glial system in fruit flies, we analyzed the toxicity of various C9orf72 mutants. Our findings demonstrate that surface glia, a model for the blood–brain barrier in vertebrates, exhibit heightened vulnerability to the expression of dipeptide repeat (DPR) originating from the mutant C9orf72 gene. This susceptibility results in pronounced developmental toxicity, as well as deficits in adult motor function and reduced lifespan. Significantly, the expression of GR100 DPR in surface glia did not lead to massive cell death of neurons or glia in the central nervous system. Additionally, the drug ursodeoxycholic acid (UDCA), which is intended to rescue the pan-neuronal Drosophila model, tended to negatively impact the locomotor activity and lifespan of glial cell models. Our findings suggest that glial cells may play a more substantial role in ALS-FTD pathogenesis than previously recognized, offering new avenues for therapeutic intervention.

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Triple-negative breast cancer (TNBC) represents a challenging subtype of breast cancer. High heterogeneity and lack of effective targeted therapies leave TNBC treatment a big challenge.1 However, repurposing existing drugs clinically proven to be safe and have low or no side effects is a potential choice.2 Recent research has also highlighted the potential benefits of combining pharmacological agents to enhance therapeutic outcomes.3 Studies show that ciclopirox olamine (CPX), an off-patent anti-fungal drug, and metformin (Met), a safe and first-line drug for treating type II diabetes, both can activate the apoptotic pathways. However, whether the combinations would exert potent anti-tumor activity against TNBC remains unclear. Here, we investigated the combinatorial anti-tumor effects of CPX and Met on TNBC. Our studies uncovered a synergistic impact of CPX in combination with Met, which resulted in a more profound inhibition of TNBC cell proliferation and a significantly enhanced apoptosis. The combinations activate both intrinsic and extrinsic apoptotic pathways in a caspase-dependent manner. Moreover, in a TNBC-derived tumor xenograft model, the combination, as compared with a single agent, potently suppressed tumor growth. Collectively, we demonstrate that the combinations of CPX and Met exhibit synergistic anti-tumor activity against TNBC in vitro and in vivo.

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Glioblastoma multiforme (GBM), defined as IDH-wild-type diffuse gliomas (WHO CNS grade IV), is the most common and aggressive primary brain tumor.1 Age significantly influences GBM, with mutational landscape varied by age.2 One of the most significant updates in the 2021 WHO classification is the division of diffuse gliomas into pediatric-type and adult-type gliomas, reflecting the growing understanding of their distinct molecular drivers and prognostic implications.1 Low-grade gliomas are more common in children, with only a 7% rate of malignant transformation from low-grade gliomas, while adults are more commonly linked to high-grade gliomas and have a transformation rate of at least 50%, resulting in a higher incidence of secondary GBM. Compared with adult GBM, pediatric GBM primarily shows PDGFRA amplification, lacks EGFR amplification, PTEN, and IDH1 hotspot mutations, and has a higher frequency of chromosome 1q gain along with lower frequencies of chromosome 7 gain and 10 loss.3 Despite significant advancements in GBM research, studies with large cohorts examining the impact of age on mutational profiles and clinical characteristics in adult-type GBM remain limited. In this study, we conducted an in-depth analysis of the characteristics of early-onset and late-onset GBM using a large-scale in-house GBM cohort alongside the GBM cohort from The Cancer Genome Atlas (TCGA) database.

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Nephronophthisis (NPHP) is an autosomal recessive kidney disease and is the most prevalent monogenic cause of end-stage renal disease in childhood. The tetratricopeptide repeat domain 21B (TTC21B) gene encodes the ciliary protein intraflagellar transport protein 139 (IFT139) and has been recently implicated in heterogeneous diseases, including nephronophthisis type 12 (NPHP12), short-rib thoracic dysplasia 4 (SRTD4), and Joubert syndrome (JBTS).1,2 In Europe and North Africa, the prevalent TTC21B variant c.626C > T (p.P209L) has been associated with focal segmental glomerulosclerosis in adults.2,3 To date, only a limited number of TTC21B gene variants have been reported in Chinese individuals, predominantly presenting with infantile NPHP, which differs from the manifestations observed in Caucasian patients.4,5 In this study, we identified novel TTC21B gene variants in Chinese children with NPHP and investigated their role in left-right asymmetry and pronephric development.

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Systemic amyloidosis is a heterogeneous group of diseases characterized by localized or systemic deposition of insoluble extracellular fibrillary proteins in organs. Systemic amyloidosis is categorized by precursor protein, and the most common are immunoglobulin light-chain amyloidosis (AL) and transthyretin (TTR) protein produced predominantly in the liver (ATTR amyloidosis). ATTR amyloidosis frequently results from age-related misfolding of wild-type TTR and, less commonly, from misfolding of a variant TTR from an autosomal dominant mutation of the TTR gene.1 Hereditary ATTR (hATTR) is a progressive and potentially fatal disease with a heterogeneous clinical presentation; patients often develop a mixed phenotype of polyneuropathy (PN) characterized by sensory, motor, and autonomic neuropathy and/or cardiac amyloidosis.1 The survival rate varies widely, ranging from 3 to 15 years after diagnosis, depending on factors such as genetic mutation and clinical phenotype. It is extremely critical for the detection of amyloidosis at the earliest stage, when therapy is still effective before severe organ damage occurs.

166

Our research focused on the impact of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway on retinal inflammation and employed an endotoxin-induced uveitis (EIU) model. EIU was provoked in mice through the intravitreal administration of lipopolysaccharide. Transcriptome analysis was performed via bulk RNA sequencing. Cytosolic mitochondrial DNA levels in the retina were quantified via PCR. Western blotting was used to assess the activation of cGAS‒STING signaling at specified times after intravitreal lipopolysaccharide injection. To understand the influence of the cGAS‒STING pathway on inflammatory retinal disorders, Cgas knockout mice were developed. Fundus imaging and fluorescein angiography were conducted to observe vitreous inflammation. Microstructural analysis of the eyes was performed, and histopathological scoring was performed. Retinal leukocytosis assays were used to evaluate retinal inflammation. Analysis of these differentially expressed mRNAs revealed activation of the cGAS‒STING signaling pathway, which was confirmed by western blotting analysis of these proteins. Using Cgas knockout mice, we observed significant inhibition of endotoxin-induced intraocular inflammation, including reduced vitreous inflammation, reduced retinal vascular leakage, decreased leukocyte adhesion, inhibited infiltration and activation of macrophages in the retina, and inhibited microglial activation. These findings suggest that cGAS might be a potential novel therapeutic target for uveitis.

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Mesenchymal stem cells (MSCs) are widely used in regenerative therapy but face limitations like low abundance, replicative senescence, donor variability, and restricted plasticity. Induced pluripotent stem cell-derived MSCs (iMSCs) may provide an alternative, but their similarities or intrinsic differences with adult MSCs remain unknown. This study compares the chondrogenic potential of iMSCs derived from chondrocyte-specific induced pluripotent stem cells, with bone marrow-derived MSCs, adipose-derived stem cells, and dedifferentiated chondrocytes. Chondrogenic differentiation was performed in high-density pellet cultures with short-term or long-term TGFβ3 treatment. Chondrogenic gene arrays, gene regulatory networks, and gene ontology analysis revealed divergent signaling pathways. Bulk RNA sequencing was performed to characterize the transcriptomic profiles of each MSC. Results showed that iMSCs produced cartilage with hyaline-like features and minimal hypertrophy, distinguishing them phenotypically from adult MSCs. Gene regulatory network analyses identified EGF, FGFR, FLT1, and HIFA as iMSC hub genes for chondrogenic differentiation. Molecular signaling analysis unveiled that TGFβ3 induced SMAD2/3, not SMAD1/5, suppressing hypertrophy in iMSC chondrogenesis. RNA sequencing highlighted cell-specific differences, functional heterogeneity, and divergent cell signaling profiles between iMSCs and adult MSCs. Using integrated transcriptome and proteome analyses, we identified and validated eight novel non-classical CD markers that may help further characterize MSCs and potentially discriminate iMSCs from other cell types. This study further advanced our understanding of MSC behaviors, emphasizing the importance of origin-specific considerations and refining the molecular description of iMSCs as an unlimited source of chondroprogenitors for cartilage regeneration.

163

Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.

160

This work aims to investigate the energy metabolism in mice with restrictive cardiomyopathy induced by cardiac troponin I (cTnI) R193H mutation. Echocardiography was used to monitor cardiac function. ATP content and ATPase activity were detected with relevant kits. The expression levels of GLUT4, FAT/CD36, and PI3K/AKT pathway proteins were detected. Proteomics and phosphorylation omics were used to analyze the differential expression and modification of cardiac proteins and related pathways, respectively. The utilization of cardiac energy substrates was investigated using relevant kits. The isovolumic relaxation time of 4-month-old cTnI193His-M mice was significantly prolonged (P < 0.01); Cardiac ATP content, ATPase activity, and mitochondrial number were significantly increased (P < 0.05, P < 0.01, and P < 0.01, respectively); GLUT4 expression level increased (P < 0.01); the expression level of CD36 decreased (P < 0.01). Proteomic results showed that the glycolytic/gluconeogenic pathway was up-regulated. Phosphorylation omics was enriched in the inositol phosphate metabolism pathway and PI3K/AKT pathway. In conclusion, at the early stage of diastolic dysfunction, cTnI193His-M mice may increase glucose uptake and metabolism through the PI3K/AKT pathway to satisfy the high energy demand, which may contribute to the development of myocardial fibrosis and heart failure.

180

Gastric cancer (GC) is a significant global health challenge due to its high incidence and mortality rate. However, the existing classification methods for GC still have limitations. Given the pivotal role of aberrant glycosylation in GC progression, there is a compelling need to develop a novel molecular classification for this disease. Using a comprehensive analysis of 186 glycogenes across seven public datasets encompassing 1547 GC patients, a 12-glycogene signature-based molecular classification was established, which was linked to tumor stage and prognosis. Among them, the overexpression of glucoside xylosyltransferase 2 (GXYLT2) was positively associated with tumor stage, diffuse subtype, and unfavorable survival outcomes in GC patients. Furthermore, GXYLT2 depletion significantly inhibited the proliferation, invasion, and sphere formation capacities in HGC-27, MKN1, and MKN45 GC cells with diffuse-subtype features, whereas its ectopic expression in AGS and MKN74 GC cells with intestinal subtype did not enhance their aggressive properties. Moreover, RNA sequencing analysis revealed that GXYLT2 knockdown resulted in the decrease of Wnt/β-catenin signaling, which was corroborated by TOPFlash reporter activity, β-catenin phosphorylation, immunofluorescence staining, and nuclear-cytoplasmic separation assays for its nuclear location, via the activation of PP2A complex dependent on GXYLT2-PP2A Aα interaction. Notably, GXYLT2 knockdown significantly suppressed tumorigenicity in vivo. Taken together, we identified GXYLT2 as a potential prognostic biomarker for GC patients, and targeting GXYLT2 suppressed the tumor aggressiveness and inhibited the Wnt/β-catenin pathway, which may provide a potential therapeutic target for GC patients.

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Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS). We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3 × Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps). Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.

172

Androgen deprivation therapies targeting the androgen receptor (AR) signaling pathway are the primary treatment strategy for prostate cancer. However, these therapies often lead to castration resistance. Developing novel agents targeting AR-independent oncogenes is critical to address this challenge, particularly for advanced castration-resistant prostate cancer. This study identified three potential tumor drivers of advanced prostate cancer, including CDC20, DTL, and RRM2, through integrative bioinformatic screening that considered gene dependency using CRISPRi/RNAi database, clinical relevance, and experimental validation with CRISPR-Cas13-mediated gene ablation. Further mechanistic studies revealed that CDC20, DTL, and RRM2 were transcriptionally regulated by the RB1/E2F1 axis, mediating cell cycle progression in prostate cancer. Additionally, we identified novel agents targeting these candidates through virtual screening and drug-sensitive tests, utilizing our established small-molecule library. These agents exhibited superior anti-tumor efficacy compared with AR antagonists in vitro. Our study identified novel prostate cancer therapeutic targets independent of the AR signaling pathway and established a research paradigm for developing anti-tumor agents through integrative cancer bioinformatics and network pharmacology analysis.

160

Hypoxia-induced right ventricular (RV) remodeling and dysfunction present a significant health risk to populations experiencing prolonged hypoxic conditions. Intense light, a noninvasive and easily implemented intervention, has previously been reported to exert cardioprotective effects by improving myocardial ischemia. However, whether intense light provides protective benefits against RV remodeling and the underlying mechanisms remain largely unexplored. In this study, we established mouse models exhibiting RV remodeling and dysfunction through long-term hypoxia to investigate the protective effects of intense light. Echocardiography, hemodynamic parameters measurements, and Fulton index assessments were employed to evaluate RV dysfunction and remodeling. Additionally, single-nuclei RNA sequencing, immunohistochemistry, immunofluorescence, and western blotting analyses were conducted to identify targeted genes in macrophage-associated inflammation within the heart. The results indicate that intense light significantly alleviates hypoxia-induced RV remodeling and dysfunction in mice. Intense light may mediate macrophage-associated inflammation through differentially expressed genes, including PF4, as well as the quantity of macrophages in the right ventricles (RVes). Resident macrophages (Res_Macro) demonstrate cardioprotective effects when intense light is applied, which mitigates RV remodeling. Our findings also suggest that PF4 expression and the presence of PF4+ resident macrophages (Res_PF4+_Macro) are linked to the attenuation of RV remodeling by intense light. Macrophage PF4 expression and the quantity of PF4+ macrophages in the RVes are closely associated with the levels of RV remodeling and dysfunction. This study unveils a novel noninvasive approach for the prevention of RV remodeling and dysfunction induced by hypoxia, and indicates that Res_PF4+_Macro and PF4 expression could be potential intervening targets.

151

Colorectal cancer (CRC) poses a significant global health challenge, with liver metastasis being a major contributor to its high mortality rate. The liver, due to its strategic anatomical location, distinctive tissue architecture, and unique metabolic properties, is the primary site for CRC to metastasize. The objective of this study was to identify hub genes involved in colorectal liver metastasis (CRLM) using a combination of bioinformatics analysis and experimental methods, and to decipher their molecular mechanisms that regulate this metastatic process. By mining data from the TCGA and GEO databases, we identified that low expression of 3-ketoacid CoA transferase 1 (OXCT1) might related to the development of CRLM. Both in vitro and in vivo experiments have indicated that the downregulation of OXCT1 significantly enhanced tumor migration and metastasis, suggesting a potential tumor-suppressive role for OXCT1 in the progression of CRLM. Further bioinformatics analysis, dual-luciferase reporter assays, and Western blot identified Yin Yang 1 (YY1) as a transcription factor regulating OXCT1 in CRC. RNA sequencing suggested that OXCT1 suppressed the Wnt signaling pathway by downregulating CDK8 expression, and diminishing its interaction with β-catenin. Additionally, OXCT1 governed CDK8 expression via histone H3 acetylation. Finally, OXCT1 expression was significantly reduced in CRLM sites, which correlated with unfavorable outcomes. Our research suggested the OXCT1/Wnt signaling axis pathway as a critical regulator of CRLM. And these findings offered valuable insights, and potential therapeutic targets for CRLM.

171

We aimed to investigate the effects and mechanism(s) of macrophage κ-opioid receptor (κ-OR) on macrophage inflammatory response and hypoxic pulmonary hypertension (HPH). Macrophage κ-OR-deficient mice (κ-ORΔMac) and their wild-type control mice (κ-ORfl/fl) were subjected to HPH or control groups. Mice with HPH presented significantly decreased expression of κ-OR in peritoneal macrophages. Compared with the κ-ORfl/fl + control group, the κ-ORfl/fl + HPH group presented increased right ventricular pressure, pulmonary vascular remodeling, and right ventricular hypertrophy and dysfunction; infiltration of M1 macrophages around pulmonary vessels; increased NLRP3 protein expression; and the release of the inflammatory cytokines. Macrophage κ-OR deficiency significantly aggravated the phenomenon mentioned above. At the cellular level, macrophages with κ-OR deficiency also aggravated lipopolysaccharide-induced inflammation. In addition, administering the κ-OR-selective agonist U50,488H significantly inhibited the inflammatory response in macrophages. The co-culture experiments revealed that U50,488H-treated macrophages inhibited the proliferation of pulmonary artery smooth muscle cells. Furthermore, our RNA sequencing and western blotting results revealed that κ-OR increases stearoyl coenzyme desaturase 1 (SCD1) expression in macrophages. Macrophage κ-OR knockdown significantly decreased SCD1 expression both in the lung tissues of HPH mice and in cultured macrophages. Moreover, SCD1 overexpression significantly suppressed the inflammatory response in lipopolysaccharide-treated macrophages, whereas the pharmacological inhibition of SCD1 increased the response. These results demonstrated that macrophage κ-OR inhibited HPH and right heart dysfunction by up-regulating SCD1, which inhibited macrophage inflammatory responses and pulmonary artery smooth muscle cell proliferation. This study provides more evidence to support the potential therapeutic role of κ-OR activation in the treatment of HPH.

157

Emerging evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) is strongly associated with the occurrence and progression of breast cancer. Herein, we identified ubiquitin specific peptidase 30 antisense RNA 1 (USP30-AS1) as a markedly upregulated lncRNA in breast cancer tissues, and the transcription factor SPI1 functions upstream to regulate the expression of USP30-AS1. Gene set enrichment analysis suggests that USP30-AS1 may regulate cell proliferation. Knockdown of USP30-AS1 suppresses breast cancer cell proliferation and tumor growth by up-regulating CDKN1A/p21. Mechanistically, USP30-AS1 exhibits dual localization within breast cancer cells. In the cytoplasm, it interacts with HnRNPF, disrupting its binding to the p21 3′UTR, which destabilizes p21 mRNA and ultimately reduces p21 expression. In the nucleus, USP30-AS1 suppresses p21 transcription by enhancing the activity of c-Myc, a known transcriptional repressor of p21. USP30-AS1 binds to enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, and prevents EZH2 from binding to the c-Myc promoter. This promotes epigenetic up-regulation of c-Myc by reducing H3K27 trimethylation. Together, these findings demonstrate the critical role of USP30-AS1 in breast cancer progression through HnRNPF/p21 and EZH2/c-Myc/p21 axes, highlighting its potential as a therapeutic target for breast cancer treatment.

157

Renal ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury, and the inflammatory response is considered a key factor. The selenoprotein GPX3, a member of the glutathione peroxidase family, has gradually attracted attention for its anti-inflammatory properties. However, the relationship between GPX3 and the inflammatory response during renal IRI remains unclear. The present study aims to investigate the role of GPX3 on the inflammatory response during renal IRI and related mechanisms. We utilized classic rat models of kidney IRI and cellular hypoxia reoxygenation model. After overexpressing GPX3 via lentiviruses and adeno-associated viruses, we observed a significant reduction in the expression levels of inflammatory factors in renal tissues, along with an increase in the expression of anti-inflammatory factor IL-10, resulting in noticeable alleviation of renal IRI. Meanwhile, we found that GPX3 alleviated the inflammatory response, probably by inhibiting the MAPK signaling pathway and reducing the expression of NAPDH oxidase. To further validate the mechanism by which GPX3 alleviated the inflammatory response, we used the MAPK signaling pathway agonist anisomycin for intervention. The results showed that anisomycin intervention significantly reversed the inhibitory effect of GPX3 on the MAPK signaling pathway, in which the expression level of NADPH oxidase was significantly increased, the secretion of inflammatory factors was increased, and the degree of renal tissue damage was significantly increased. These findings suggest that selenoprotein GPX3 alleviates inflammation during renal IRI by inhibiting the MAPK signaling pathway and reducing NADPH oxidase expression.

175

P21-activated kinase 1 (PAK1) plays an oncogenic role in colorectal cancer (CRC). However, the role of PAK1 in CRC progression remains incompletely understood. Here, we showed that PAK1 enhanced the mRNA stability of multiple oncogenic factors. We found that PAK1 promoted CRC initiation and progression as previously reported. Mechanistically, loss of PAK1 promoted mRNA decay and inhibited the expression of CD44, SAA1, MTOR, RPS6KB1, and EIF4G1, the factors involved in tumorigenesis in many cancers. Importantly, our results revealed that the PAK1 inhibitor, PF3758309, exhibited a profound synergistic effect with oxaliplatin in CRC. Collectively, our study unveils a novel function of PAK1 in CRC progression. Thus, these results highlight the potential of targeting PAK1 as a therapeutic strategy in CRC, particularly in combination with oxaliplatin.

155

While the dynamic interaction between long non-coding RNA (lncRNA) and RNA binding proteins is widely recognized as pivotal in the regulation of hepatocellular carcinoma (HCC), the precise underlying mechanisms and networks governing their effects remain elusive. Here, we have uncovered LINC00862, a novel lncRNA that exhibits pronounced down-regulation in HCC tissues and whose expression levels are linked positively to favorable HCC outcomes, as a function of tumor stage and size. Through functional assays, we have established the anti-tumor effects of LINC00862 on HCC processes such as proliferation, invasion, metastasis, and growth in vitro and in vivo. Mechanistically, RNA sequencing and quantitative proteomics analyses have revealed that LINC00862's downstream target effector in HCC cells is RBM47. Our further experimentation strongly supports RBM47 as a central mediator of LINC00862's tumor-suppressive effects. Furthermore, our study elucidates the ability of LINC00862 to engage in Hoogsteen pairing interaction with the RBM47 promoter, while simultaneously recruiting the transcription factor CHD5 to elicit RBM47 transcriptional activation, ultimately resulting in transcriptional up-regulation and its consequential expression in hepatoma cells. It is intriguing to note that we also discovered that RBM47 could act as a transcription factor, positively regulating LINC00862 expression. Our identification of a positive feedback loop involving LINC00862 and RBM47 expands our comprehension of the intricate regulatory network that shapes HCC pathogenesis. LINC00862 represents a promising molecular marker for HCC diagnosis and therapeutics.

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Glucocorticoid-induced osteoporosis (GIOP) is a public health problem that needs urgently to be resolved, and oxidative stress is closely related to osteogenic impairment. TP53-induced glycolysis and apoptosis regulator (TIGAR) contributes to the occurrence and development of various diseases by reducing reactive oxygen species (ROS). However, it is unknown whether and how TIGAR plays a regulatory role in GIOP. The aim of the present study is to investigate the role of TIGAR in osteogenic differentiation and the underlying molecular mechanism. We explored the protective role and mechanism of TIGAR on osteogenic differentiation and GIOP by using the TIGAR overexpression plasmid and siRNA in vitro, and by constructing systemic TIGAR overexpression (TG-TIGAR) mice in vivo, respectively. In conclusion, our study clarified that TIGAR promotes osteogenic differentiation and improves GIOP by upregulating autophagy-nuclear factor erythroid-2 related factor (Nrf2)-ROS pathway, suggesting that TIGRA may be a potential therapeutic target for GIOP treatment.

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Snail is a core inducer of epithelial-to-mesenchymal transition. Here, we show that UBR5 promotes ubiquitin-mediated degradation of Snail and regulates the progression of colorectal cancer cells through its E3 ubiquitin ligase function. UBR5 specifically binds to Snail in vitro, but not Slug, and its degradation depends on snail phosphorylation. Depletion of endogenous UBR5 causes Snail protein accumulation, epithelial-to-mesenchymal transition, and tumor invasion in colorectal cancer cells. Conversely, the overexpression of UBR5 reduces Snail protein abundance and cellular invasiveness. The activity-deficient mutant UBR5 C2768S disrupts its binding and degradation to Snail, thereby losing the ability to regulate epithelial-to-mesenchymal transition in colorectal cancer cells. UBR5 is lowly expressed in human colorectal cancer versus normal tissues, and high UBR5 levels correlate with favorable prognosis, suggesting that UBR5 sustains the epithelial state and inhibits cancer progression. These findings establish the UBR5-Snail axis as a mechanism of post-translational regulation of epithelial-to-mesenchymal transition and colorectal cancer metastasis.

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The authors regret that the given names and family names of all authors in original article were inadvertently switched. The correct order of the given and family names is provided in this document. Rodriguez-Jimenez Francisco Javier, Artero-Castro Ana, Studenovska Hana, Selles Francisca, Arteaga Claramunt Alba Maria, Brymova Anna, Jendelova Pavla, Motlik Jan, Petrovski Goran, Lytvynchuk Lyubomyr, Ardan Taras, Tichotová Lucie, Drutovič Saskia, Sharma Ruchi, Lukovic Dunja, Bharti Kapil, Erceg Slaven. The authors apologize for any inconvenience this may have caused.

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