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。

过刊浏览

The origin of bone marrow osteoblasts is not totally understood. Recent findings demonstrated that bone marrow osteoblasts could be derived from a subpopulation of hypertrophic Col2+/Col10+ chondrocytes which migrate from the growth plate into the bone marrow cavity underneath the growth plate and dedifferentiate into mesenchymal progenitor cells and then differentiate into mature osteoblasts.1 This process is called chondrocyte-osteoblast transdifferentiation. This type of osteoblast participates in bone formation and is involved in maintaining bone remodeling, especially in the epiphyseal and diaphyseal regions of long bone. Several growth factors, such as Ihh, PTH, and Wnt signaling molecules have been demonstrated to play a critical role in the regulation of chondrocyte-osteoblast transdifferentiation2; however, the role of Runx2, the key transcription factor controlling skeletal development,3 in chondrocyte-osteoblast transdifferentiation has not been fully defined.

Pancreatic cancer is one of the most lethal cancers worldwide and is characterized by a poor prognosis.1,2 Due to its aggressive nature and lack of early symptoms, most patients are diagnosed at an advanced stage, and chemotherapy is the optimal option.3,4 Epidemiology, the incidence rate of pancreatic cancer has increased in the last two decades, from 196,000 patients in 1990 to 441,000 in 2017. Based on 2020 global cancer statistics, the annual cases of pancreatic cancer have increased to 195,773.4 Unfortunately, patients demonstrate resistance to chemotherapy, and only some of them benefit from current therapeutic strategies.5 Systemic chemotherapy has been widely applied for the treatment of pancreatic cancer. However, inter- and intratumoral heterogeneity, especially changes in genomic and immunological profiles, can lead to therapeutic resistance. Moreover, SMAD4, BRCA1/2, and PALB2 mutations have been associated with therapy resistance in pancreatic cancer.4 This highlights the urgent need to explore the underlying mechanisms of chemoresistance and to develop innovative therapeutic strategies.

Mantle cell lymphoma (MCL) is recognized as one of the most genetically heterogeneous diseases, with high instability at the genomic level. MCL is common in males with a male-to-female ratio of about 2:1, and its incidence accounts for 3%–10% of adult non-Hodgkin lymphoma cases. The evolutionary dynamics of MCL clones at the single-cell level remain largely unclear. Our research suggests that MCL may arise from multiple cells within the abnormal microenvironment of the entire hematopoietic lineage, particularly from initiating cells. These initiating cells predominantly consist of CD19−/IgM− subclones and exhibit a disrupted malignant clonal differentiation of pre-B cells along the tumor immunity evolution tree. Based on the single-cell transcriptome sequencing on the RedRock capture platform, we established the JeKo-1-LZ1 model, revealed the JeKo-1-LZ1 biology characteristics, and verified that the JeKo-1-LZ1 model was more representative than the JeKo-1-spheroid model by flow cytometry and sorting, colony forming experiment, and immunohistochemical and function analyses. Further details of our methodology can be found in the supplementary materials.

DNA methylation is one of the mechanisms of epigenetic control of gene expression, and a change in the intrinsic pattern can lead to various diseases and disorders. At the same time, this makes DNA methylation a disease-specific biomarker. For a long time, prostate-specific antigen (PSA) was used as an established tumor marker for prostate adenocarcinoma in the clinic for the diagnosis of prostate cancer (PCa).1 Despite the generally accepted fact that PSA is organ- but not cancer-specific, it still retains its diagnostic value for cancer detection.2 Here, we show that the acquisition of biallelic methylation status or even biallelic lack of methylation by the PSA promoter is a characteristic feature of cancer cells, while the monoallelic distribution of CpG/CCWGG methylation in the PSA promoter is a hallmark of noncancerous conditions. The coexisting CpG/CCWGG monoallelic methylation may indicate that CCWGG may represent a new signaling event for monoallelic methylation, suggesting novel functionality of this mark or representing benign prostatic hypertrophy conditions. In this study, we demonstrate that the methylation status of the non-CpG island PSA promoter spanning from −393 to +51 nucleotide positions, possessing 6 CpGs and 5 CCWGG epigenetic marks, has a distinctive methylation pattern in a PCa cell line model.

Cornelia de Lange Syndrome (CdLS) is an intellectual disability syndrome characterized by distinctive clinical features including growth retardation, limb malformation, and a characteristic facial dysmorphism.1 Six genes, including NIPBL and MAU2, are associated with CdLS, all encoding components or partners of the cohesin protein complex. Cohesins play a central role in gene expression regulation by organizing chromatin and modulating transcription.2 CdLS is classified as a transcriptomopathy due to dysregulated transcription resulting from pathogenic variants in cohesin-related genes. NIPBL mutations are the most common cause of CdLS, impairing cohesin loading onto DNA. Previous transcriptomic studies have identified deregulated genes in CdLS (e.g., Liu et al3 or Mills et al4), but none have comprehensively assessed the impact of various NIPBL variants, including missense mutations, on isogenic induced pluripotent stem cells (iPSCs). In this study, we investigated mRNA and protein levels of NIPBL and MAU2, along with transcriptomic consequences of multiple NIPBL pathogenic variants, in isogenic iPSCs. Our findings confirm the role of NIPBL and MAU2 in CdLS pathogenesis and highlight deregulated genes contributing to the syndrome's phenotype.

The autism susceptibility candidate 2 (AUTS2) gene1,2 at 7q11.2 was first identified and found disrupted because of a balanced translocation in a pair of monozygotic twins with autism spectrum disorder (ASD). Analysis of 60 novel cases suggests that clinical phenotypes are more closely associated with intellectual disability rather than directly linked to ASD features. Human AUTS2 is a highly conserved gene that spans 1.2 Mb. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa). Phenotypic analysis of patients indicated that they had borderline to severe intellectual disability/developmental delay, and 83%–100% had microcephaly. Mild dysmorphology was present. Specific traits of autism (like obsessive behavior) were seen frequently (83%). AUTS2 is also associated with alcohol consumption, heroin dependence, schizophrenia, and dyslexia, as analyzed using GWAS studies.

Pancreatic cancer (PC) is a commonly malignant tumor with a 5-year survival rate of only 10%.1 Cuproptosis is a newly discovered cell death mechanism closely associated with the development of tumors. This study mainly aimed to investigate cuproptosis-related genes (CRGs) and found the marker genes to construct a prognostic model for PC patients. Meanwhile, we explored their roles in immune infiltration and their relationship with drug sensitivity. After comparing the expression patterns of ten CRGs, we found these genes were differently expressed between the tumor and normal tissues. Then we further performed functional enrichment analysis, cluster analysis, and immuno–infiltration correlation analysis. We found that cyclin-dependent kinase inhibitor 2A (CDKN2A) had the highest mutation frequency and was significantly down-regulated in tumor samples. Besides, high expression of dihydrolipoamide S-acetyltransferase (DLAT) was associated with a worse prognosis by Kaplan–Meier survival analysis. Finally, we constructed a prognostic model based on these CRGs. In the 1-year, 3-year, and 5-year receiver operator characteristic curves, the predictive accuracy of evaluation of the area under a receiver operating characteristic curve was 0.638, 0.690, and 0.796, respectively. Besides, we identified 30 potential gene mutation regulators and obtained the differences in immune microenvironment and drug sensitivity in different risk groups, which provided references for PC prediction, immunotherapy, drug therapy, and gene therapy.

The interaction of lactate metabolism with immunity plays a crucial role in the remodeling of the immune microenvironment and even in the heterogeneous progression of hepatocellular carcinoma (HCC). The intratumor-accumulated lactate served a vital role in the inefficacy of antitumor immune responses, the aggressiveness of tumor cells, and immunotherapy.1 Furthermore, lactate generated from the tumor microenvironment can be used as fuel for the proliferation and infiltration of immunosuppressive cells.2 Previous studies regarding the taxonomies of HCC, solely from the perspective of lactate3 or tumor immune microenvironment4 may introduce the potential for bias in the comprehension of HCC heterogeneity. Thus, deciphering the crosstalk properties between lactate and immune is imperative.

Hypertrophic scar and keloid are a major medical problem, which may lead to disfigurement, growth restriction, and permanent loss of function, causing severe physical, psychological, and economic burdens.1 When skin injury occurs, the wound heals through a dynamic series of physiological events, including blood clotting, granulation tissue formation, re-epithelialization, and extracellular matrix remodeling.2 However, the newly formed extracellular matrix in a scar may never achieve the flexibility or strength of the original tissue. Prior studies have suggested that the fibrotic process that occurs after skin injury may be mediated by a specific lineage of scar-prone fibroblasts in the dermis, which are responsible for scar deposition, namely engrailed-1 (EN-1) lineage-positive fibroblasts (EPFs).3 EN-1 is a transcription factor and plays an important role in embryonic development. In most cell types, EN-1 expression is limited to embryonic development. However, under pathological conditions, EN-1 can be re-expressed to promote phenotypic adaptation.4 The mechanical signaling factor YAP is associated with EPFs, establishing a link between mechanical transduction and fibrosis. Recent studies have demonstrated that EPFs play a key role in scar formation and that inhibition of YAP/EN-1 could restrict the formation of scar.5 However, as a downstream transcriptional factor of the YAP/TAZ pathway, EN-1's role in the pathological activation of fibroblasts and scar formation remains unclear. In this study, we investigated whether inhibition of EN-1 expression would be sufficient to suppress TGFβ1-induced fibroblast activation, extracellular matrix production, and scar formation in a skin injury model.

Sarcoma is a kind of mesenchymal malignant tumor and often has poor chemotherapy response. There are many reasons for the insensitivity of sarcomas to chemotherapy, among which genetic changes are important. As a common type of gene alteration, gene fusion plays an important role in the pathogenesis and progression of tumors. In this study, we report a novel osteosarcoma-associated fusion gene, EWSR1-PSMC5, found in patients insensitive to chemotherapy. This gene is a novel fusion mode and has been found to play an important role in autophagy activation. The fusion gene may lead to the activation of autophagy through various signaling pathways, thus leading to the development of osteosarcoma resistance. We report this new fusion mode for the first time, and it should be noted that there is a less common report of EWSR1-related fusion gene in osteosarcoma.

Microtia, a congenital malformation affecting the external and middle ear, arises from disruptions during the development of embryonic branchial arches and cranial neural crest cells (CNCCs), making it the second most prevalent maxillofacial birth defect and a leading cause of conductive hearing loss.1 Aberrant gene expression is pivotal in microtia pathogenesis by influencing chondrocyte activities. Homeobox (HOX) genes stand out as regulators for proper skeletal patterning, and mutations within the HOX family have been implicated in microtia.2 Our transcriptomic microarray analysis of microtia revealed a substantial reduction in HOXB6 expression in auricle cartilage.3 HOXB6, known for its crucial involvement in embryonic axis determination, when expressed ubiquitously in transgenic mice, resulted in microtia. However, the specific role of HOXB6 in microtia remains elusive. This study validates the down-regulation of HOXB6 in auricle cartilage obtained from microtia patients. We also postulate that the decrease observed in HOXB6 expression levels, resulting from a reduction in retinoic acid (RA) pathway signaling, triggers the inhibition of chondrocyte proliferation and the promotion of apoptosis by directly governing the expression of targeted genes related to these cellular behaviors. This action leads to a decrease in the overall chondrocyte population, contributing to the phenotypes observed in microtia patients.

Alzheimer's disease (AD) remains clinically incurable, raising a significant public health issue, particularly with its continuously increased incidence.1 Inflammatory bowel disease, including ulcerative colitis and Crohn's disease (CD), is characterized by long-standing inflammation and immunological imbalance of the gastrointestinal system.2 Recent epidemiological studies suggest a link between increased AD risk and inflammatory bowel disease.3,4 Due to the unclear regulatory mechanism potentially connecting AD with inflammatory bowel disease, this study is designed to reveal the underlying mechanisms at the genetic level and identify diagnostic markers to predict the risk of developing AD in patients with CD. Gene expression data of AD (GSE109887) and CD (GSE95095) were obtained from the GEO database for further bioinformatics analyses, including differentially expressed gene (DEG) identification, weighted gene co-expression network analysis, protein–protein interaction network construction, enrichment analyses, and immune infiltration. Least absolute shrinkage and selection operator (LASSO) regression was employed to filter hub genes in conjunction with another machine learning algorithm, random forest. Then, a nomogram was constructed and validated to assess the diagnostic value. Consequently, we identified four hub genes (PDGFRB, BCL6, DDIT4L, TMEM106A) strongly related to AD with CD, and constructed a credible diagnostic model based on these genes. Distinct but interrelated pathways were revealed in the pathological process of AD with CD, providing new perspectives on the molecular mechanisms linking these two diseases and underscoring the importance of further investigation of these shared genetic pathways. Moreover, the developed nomogram could assist clinical decision-making and highlight potential therapeutic targets for AD in CD patients. Figure S1 provides a concise overview of our research process.

Otoancorin (OTOA) is a glycosylphosphatidylinositol (GPI)-anchored protein mediating the attachment of the tectorial membrane (TM) to the spiral limbus (SL) in the inner ear. Homozygous or compound heterozygous mutations in OTOA cause autosomal recessive deafness (DFNB22). We performed short-read exome sequencing (SRS) in a 10-month-old boy with sensorineural hearing loss, identifying a potential p.Glu787∗ variant in OTOA. Interestingly, this variant is common among normal-hearing individuals, leading us to question its pathogenic potential. We generated a knock-in mouse model for this variant and another lacking the C-terminal GPI-anchorage to study the in vivo consequences of deleting the C-terminus of Otoa. OtoaE787∗/E787∗ mice exhibited reduced transcript expression, TM detachment, and sensorineural hearing loss. Removal of the GPI-anchorage resulted in the loss of surface expression of Otoa and TM detachment, highlighting the importance of the C-terminus. To explain the discrepancy between the pathogenicity of p.Glu787∗ in the mouse model and its high allelic frequency in normal-hearing humans, we performed long-read sequencing (LRS) and identified that the variant was in a pseudogene (OTOAP1). Whole-genome sequencing revealed an inversion encompassing the 3′ end of OTOA in the patient. In summary, we demonstrated the limitations of SRS and confirmed the essential role of the Otoa C-terminus.

Ulcerative colitis (UC), a subtype of inflammatory bowel disease, arises from disrupted gut homeostasis, primarily due to an aberrant innate immune response to intestinal microbiota and an underlying genetic background.1 Recently, complete healing of mucosal inflammation has been suggested as a new therapeutic goal in UC treatment.2 However, this goal remains challenging, as approximately 20% of individuals in clinical remission still exhibit active mucosal inflammation.3 Understanding the molecular alterations underlying this persistent mucosal inflammation is crucial for advancing UC pathogenesis insights and treatment strategies. While previous studies have explored transcriptomic profiles in patients with inflammatory bowel disease,4 consistent gene expression characteristics and enriched pathways, particularly in Asian patients with UC, remain unconfirmed. Our study addresses this gap by employing RNA sequencing (RNAseq) to analyze transcriptomic changes in mucosal biopsy specimens. We compare active (UCA) and macroscopically inactive (UCI) inflammatory areas during colonoscopy in UC patients with normal controls (NC). This approach aims to uncover novel molecular insights and potential therapeutic targets, providing a deeper understanding of UC pathogenesis.

Titin, the largest known protein in nature, is a giant sarcomeric protein that plays essential architectural, developmental, and regulatory roles in striated muscles. Mutations in the TTN gene (MIM: 188840) that encodes titin are related to a broad range of muscle diseases known as titinopathies, with diverse clinical manifestations including weakness, contractures, scoliosis, respiratory failure, and cardiomyopathy.1 In this case report, we describe two sisters with severe scoliosis, both carrying novel compound heterozygous variants in the TTN gene, yet presenting distinct clinical phenotypes, adding to the growing body of evidence linking TTN mutations to scoliosis and other titin-related disorders.

This study investigates key genes contributing to lupus nephritis (LN). While extensive research has elucidated various aspects of LN pathogenesis, the specific involvement of phosphorylation-related genes (PRGs) in this context remains an area of growing interest. We employ single-cell RNA sequencing analysis on renal tissues from 24 LN patients and 10 healthy controls. Leveraging the non-negative matrix factorization (NMF) algorithm, we identified critical gene patterns and constructed 61 predictive models using a comprehensive suite of 12 machine learning algorithms. We developed a predictive model using 6 PRGs, enhanced by a LASSO plus Naive Bayes approach. These PRGs demonstrated high predictive accuracy (the area under a receiver operating characteristic curve was 0.954 and 0.845 in training and validation cohorts, respectively). One of these PRGs, CEBPB (CCAAT enhancer binding protein beta), showed significant differences in expression between LN patients and controls. Further analysis revealed correlations between CEBPB and renal function parameters. The insights of this study into gene expression patterns enhance our understanding of the molecular mechanisms and support the potential for early diagnosis and targeted treatment strategies in LN. Extensive protein–protein interaction network analysis and clinical correlations underscore the important roles of these genes in LN. Our findings underscore the potential of PRGs as biomarkers, propelling the precision medicine frontier in LN diagnostics and therapeutics.

Interferon regulatory factors (IRFs) are transcription factors with a conserved N-terminal helix-loop-helix DNA-binding domain 1. IRF family plays a pivotal role in regulating interferon transcription, immune cell development, cell growth, apoptosis, and oncogenesis.2 Despite considerable research, the roles of IRFs in cancer development, metastasis, drug resistance, and prognosis remain unclear. Through multidimensional correlation analysis, we examined the association between IRFs and various cancer characteristics, including clinical and immune subtype analysis, stemness, tumor microenvironment (TME), and drug sensitivity, by utilizing The Cancer Genome Atlas (TCGA) data. Moreover, the classification and prognostic role of IRF1 were further validated through immunohistochemistry staining of kidney renal papillary cell carcinoma (KIRP) clinical tissues. This research enriches our understanding of the IRFs' roles in cancer and their clinical applications.

The incidence of endometrial cancer (EC) is increasing, particularly in high-risk cases with poor prognosis.1 Reprogramming glucose metabolism is the main feature of energy metabolism in EC cells, resulting in substantial lactate accumulation.2 Recent research indicates that the accumulation of lactic acid during the metabolic process can serve as a substrate.3 The high concentration of lactate accumulated by metabolites can promote the malignant progression of tumor cells by modifying key proteins through lactylation.4,5 Therefore, the role of lactylation in the occurrence and development of EC is worth exploring. We found lactylation-related genes (PFKM, TXN, AKR1A1, MECP2, MDH1, GPI, GOT2, and COX4I1) that play a role in the occurrence and development of EC and constructed a lactylation score model. The lactylation score has a strong correlation with the clinicopathological features, immune cell infiltration, and genetic instability of EC based on the data in The Cancer Genome Atlas database. Our research showed that PFKM (phosphofructokinase, muscle) underwent lactylation in vitro, which promoted colony formation, invasion of Ishikawa cells, and angiogenesis of HUVEC cells. Our findings provide new molecular prognostic markers and potential therapeutic targets for EC, thereby contributing to the identification of potentially effective drugs for EC.

Myeloid-derived suppressor cells (MDSCs) constitute a crucial component of the immunosuppressive tumor microenvironment.1 Prostaglandin E2 receptor 4 (EP4) is involved in regulating immunosuppressive MDSC differentiation and is emerging as a promising target for cancer immunotherapy.2 No EP4 antagonists have been approved for anti-tumor therapy, underscoring the urgent requirement for the discovery of novel EP4 antagonists. G protein and β-arrestin represent two classical downstream pathways for EP4. The inactivity of G protein and β-arrestin serves as a readout to indicate EP4 antagonism, providing a rationale for establishing EP4 drug screening platforms. From a broad perspective on the history of G protein-coupled receptor (GPCR) drug discovery, using a β-arrestin-based drug screening strategy may offer greater advantages over G protein strategies, especially for the GPCRs that have not been proven on which G proteins they bind. Several cellular assays for the detection of GPCR/β-arrestin interaction have been established, including the PRESTO-Tango assay and fluorescent β-arrestin labeling assay. However, these assays are not suitable for the real-time dynamic detection of GPCR-β-arrestin signaling. In this study, we aimed to develop a novel real-time β-arrestin recruitment assay for EP4 receptor and to identify a potent EP4 antagonist that could attenuate the immunosuppressive effects of MDSCs.

Poor prognosis is associated with oral squamous cell carcinoma (OSCC), an aggressive form of malignant tumor.1 Developing effective targeted therapies against OSCC is anticipated to have significant clinical implications. Fisetin (3, 3′, 4′, 7-tetrahydroxyflavone), a natural flavonoid, the most common phytochemical found in a variety of fruits and vegetables, may bring several therapeutic potential benefits to people.2 Investigating the pharmacological impact of natural flavonoid fisetin on the management of OSCC was the aim of the current investigation. By focusing on the tumor-associated antigen MUC1 (mucin 1), fisetin prevents OSCC cells from transforming malignant. This study aims to provide new diagnostic indicators and therapeutic targets for the diagnosis and treatment of OSCC by exploring the role and mechanism of fisetin in OSCC.

Mutations in fibrillin-1 gene (FBN1) have been shown to be associated with Marfan syndrome and most FBN1 mutations display missense or nonsense. Recently, reports on synonymous mutation-related diseases have attracted widespread attention. Zhang et al demonstrated that synonymous mutations in saccharomyces cerevisiae have pathogenicity like non-synonymous mutations.1 Based on a special Marfan syndrome patient with a novel synonymous mutation in FNB1, this study aimed to investigate the pathogenic mechanism of synonym mutation, hoping to explore individualized precision therapy to improve or even cure those diseases caused by synonymous mutations. Through the current study, we naturally come to the following conclusions: mutations within the exon that was away from canonical splicing sites might lead to aberrant splicing, by generating splicing regulatory elements (SRE) and leading to alterations in SRE-binding proteins and thus breaking the splicing balance. Studies on the regulatory process of gene splicing in genetic diseases are expected to provide new prospects for individualized targeted therapy.

TNNI3K (troponin-I interacting kinase) encodes a duo tyrosine and serine/threonine kinase implicated in cardiomyopathy, arrhythmias, and cardiac conduction disease (CCD).1 However, no direct downstream phosphorylation targets of TNNI3K have been identified yet.2 Here, we employed the CRISPR/Cas9 gene-editing technique to generate a splicing mutation in the 4th exon of zebrafish tnni3k ortholog gene that mimics a TNNI3K splicing variant identified from a patient family with cardiomyopathy and CCD. This tnni3k heterozygous mutant (tnni3ke4/+) recapitulated several key features of cardiomyopathy and CCD, thus representing a novel model of human TNNI3K mutation-based cardiac diseases. Next, we utilized this heterozygous tnni3ke4/+ mutant to perform proteomics and phosphoproteomic analysis. As a result, we identified Mypt1/Mlc2/Yap1/Nfatc1 axis as the downstream phosphorylation targets of Tnni3k. Lastly, we found that treatment of cyclosporine A, an inhibitor of Nfatc1 translocation from cytoplasm to the nucleus, exhibited a partial cardioprotective effect on the tnni3ke4/+ heterozygous mutant. Together, we generated a unique zebrafish animal model of TNNI3K-based cardiac diseases and identified the Mypt1/Mlc2/Yap1/Nfatc1 axis as its downstream phosphorylation targets that could be potentially leveraged to develop new therapeutic strategies.

The prognosis of pancreatic cancer (PC) is difficult to predict1 and is extremely poor.2 Studies showed that cuproptosis was related to PC. The roles are not completely understood. It is considered that lncRNAs are closely associated with PC. We explored the relationship of curproptosis-related lncRNAs (CRLs) with the prognosis of PC patients and their potential role. We determined 19 prognostic CRLs through Pearson correlation analysis and univariate Cox regression analysis from 185 tumor samples. Subsequently, we constructed a predictive prognosis model for PC patients based on four CRLs and utilized the formula to calculate the risk score. The values for the area under the receiver operating characteristic (ROC) curve (AUC) were 0.699, 0.749, and 0.824 at 1 year, 3 years, and 5 years, respectively, which suggested that our risk model showed good predictive ability. Besides, we found the potential regulatory pathways by enrichment analysis, obtained the differences in immune microenvironment and drug sensitivity in different risk groups, and found that drug sensitivity in the high-risk group of other drugs was significantly lower. The prognostic model can accurately evaluate the prognosis for PC patients. These CRLs were related to the immune microenvironment, which can become underlying biomarkers for PC prediction, immunotherapy, and drug therapy.

n the mammalian heart, cardiomyocytes undergo a transient window of proliferation that leads to regenerative impairment, limiting cardiomyocyte proliferation and myocardial repair capacity. Cardiac developmental patterns exacerbate the progression of heart disease characterized by myocardial cell loss, ultimately leading to cardiac dysfunction and heart failure. Myocardial infarction causes the death of partial cardiomyocytes, which triggers an immune response to remove debris and restore tissue integrity. Interestingly, when transient myocardial injury triggers irreversible loss of cardiomyocytes, the subsequent macrophages responsible for proliferation and regeneration have a unique immune phenotype that promotes the formation of pre-existing new cardiomyocytes. During mammalian regeneration, mononuclear-derived macrophages and self-renewing resident cardiac macrophages provide multiple cytokines and molecular signals that create a regenerative environment and cellular plasticity capacity in postnatal cardiomyocytes, a pivotal strategy for achieving myocardial repair. Consistent with other human tissues, cardiac macrophages originating from the embryonic endothelium produce a hierarchy of contributions to monocyte recruitment and fate specification. In this review, we discuss the novel functions of macrophages in triggering cardiac regeneration and repair after myocardial infarction and provide recent advances and prospective insights into the phenotypic transformation and heterogeneous features involving cardiac macrophages. In conclusion, macrophages contribute critically to regeneration, repair, and remodeling, and are challenging targets for cardiovascular therapeutic interventions.

circular RNA (circRNA) is a covalently closed single-stranded RNA that lacks 5' and 3' ends and has long been considered a noncoding RNA. With the development of high-throughput sequencing and bioinformatics technology, the understanding of circRNA has become increasingly advanced. Recent studies have shown that some cytoplasmic circRNAs can be effectively translated into detectable proteins, further indicating the importance of circRNA in cellular pathology and physiological functions. Internal ribosome entry site (IRES) and N6-methyladenosine (m6A) mediated cap-independent translation initiation are considered potential mechanisms of circRNA translation. Multiple circRNAs have been shown to play crucial roles in human cancer. This paper provides an overview of the nature and functions of circRNA and describes the possible mechanisms underlying the initiation of circRNA translation. We summarized the emerging functions of circRNA-encoded proteins in human cancer. Finally, we discuss the therapeutic potential of circRNAs and the challenges of research in this field. This review on circRNA translation will reveal a hidden human proteome and enhance our understanding of the importance of circRNAs in human malignant tumors.

With the rapid advancements in second-generation gene sequencing technologies, a growing number of driver genes and associated therapeutic targets have been unveiled for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). While they are clinically classified as non-small cell lung cancer (NSCLC), they display distinct genomic features and substantial variations in clinical efficacy, underscoring the need for particular attention. Hence, this review provides a comprehensive overview of the latest advancements in driver genes, epigenetic targets, chemotherapy, targeted therapy, and immunotherapy for LUAD and LUSC. Additionally, it delves into the distinctions in signaling pathways and pivotal facets of clinical management specific to these two categories of lung cancer. Moreover, we furnish pertinent details regarding clinical trials pertaining to driver genes and epigenetics, thus establishing a theoretical foundation for the realization of precision treatments for LUAD and LUSC.

Mitochondria serve as the energy provider and enable life activities, and they are the only organelles containing extra-chromosomal DNA. Each mitochondrion contains multiple copies of its genome, which is usually referred to as mitochondrial DNA (mtDNA). mtDNA encodes necessary electron transport chain complex subunits, as well as the essential RNAs for their translation within the organelle. Therefore, the precondition for intact mitochondrial function and cardiomyocyte survival is the integrity of mtDNA. Accumulating evidence suggests that the disruption of mtDNA integrity is involved in ischemia/reperfusion-induced mitochondrial dysfunction and cardiomyocyte injury. Here, we review the current opinions about the pathways of mtDNA integrity maintenance and discuss the role of mtDNA integrity in cardiomyocyte injury reacting to ischemia/reperfusion. We also discuss the mechanisms by which mtDNA mediates ischemia/reperfusion-induced cardiomyocyte injury, together with therapeutic strategies by targeting mtDNA.

The ubiquitin (Ub) system, a ubiquitous presence across eukaryotes, plays a crucial role in the precise orchestration of diverse cellular protein processes. From steering cellular signaling pathways and orchestrating cell cycle progression to guiding receptor trafficking and modulating immune responses, this process plays a crucial role in regulating various biological functions. The dysregulation of Ub-mediated signaling pathways in prevalent cancers ushers in a spectrum of clinical outcomes ranging from tumorigenesis and metastasis to recurrence and drug resistance. Ubiquitination, a linchpin process mediated by Ub, assumes a central mantle in molding cellular signaling dynamics. It navigates transitions in biological cues and ultimately shapes the destiny of proteins. Recent years have witnessed an upsurge in the momentum surrounding the development of protein-based therapeutics aimed at targeting the Ub system under the sway of cancer stem cells. The article provides a comprehensive overview of the ongoing in-depth discussions regarding the regulation of the Ub system and its impact on the development of cancer stem cells. Amidst the tapestry of insights, the article delves into the expansive roles of E3 Ub ligases, deubiquitinases, and transcription factors entwined with cancer stem cells. Furthermore, the spotlight turns to the interplay with pivotal signaling pathways the Notch, Hedgehog, Wnt/β-catenin, and Hippo-YAP signaling pathways all play crucial roles in the regulation of cancer stem cells followed by the specific modulation of Ub-proteasome.

Ontogeny cannot be separated from mechanical forces. Cells are continuously subjected to different types of mechanical stimuli that convert into intracellular signals through mechanotransduction. As a member of the G protein-coupled receptor superfamily, adhesion G protein-coupled receptors (aGPCRs) have attracted extensive attention due to their unique extracellular domain and adhesion properties. In the past few decades, increasing evidence has indicated that sensing mechanical stimuli may be one of the main physiological activities of aGPCRs. Here, we review the general structure and activation mechanisms of these receptors and highlight the lesion manifestations relevant to each mechanosensitive aGPCR.

Endometrial carcinoma (EC) is a prevalent gynecological cancer, and its interaction with the immune system is pivotal in cancer progression. This comprehensive review explores the molecular mechanisms involved in the regulation of EC by tumor-infiltrating immune cells. This review discusses the composition and functions of various immune cell types within the tumor microenvironment, including T cells, B cells, macrophages, and natural killer cells, and elucidates their specific roles in cancer control. It also delves into the immune evasion strategies employed by EC cells, with a specific focus on immune checkpoint pathways and their influence on tumor development. Signaling pathways, cytokines, and chemokines mediating immune responses within the tumor microenvironment are also detailed. Furthermore, clinical implications and therapeutic strategies, such as immunotherapies, are also reviewed, and relevant clinical trials are discussed. Additionally, this review discusses the existing gaps in our knowledge, suggests potential avenues for future research, and emphasizes the significance of understanding these mechanisms for enhanced EC treatment. This review provides an exhaustive overview of the current knowledge, supporting the ongoing quest for more effective therapeutic interventions on EC.

Ferroptosis is an emerging form of programmed cell death triggered by iron-dependent lipid peroxidation. It is distinguished from other forms of cell death by its unique morphological changes and characteristic fine-tuned regulatory gene network. Since its pivotal involvement in the pathogenesis and therapeutic interventions of various diseases, such as malignant tumors, cardiovascular and cerebrovascular diseases, and traumatic disorders, has been well-established, ferroptosis has garnered significant attention in contemporary physiological and pathological research. For the advantage of alleviating the clinical symptoms and improving life quality, traditional Chinese medicine (TCM) holds a significant position in the treatment of these ailments. Moreover, increasing studies revealed that TCM compounds and monomers showed evident therapeutic efficacy by regulating ferroptosis via signaling pathways that tightly regulate redox reactions, iron ion homeostasis, lipid peroxidation, and glutathione metabolism. In this paper, we summarized the current knowledge of TCM compounds and monomers in regulating ferroptosis, aiming to provide a comprehensive review of disease management by TCM decoction, Chinese patent medicine, and natural products deriving from TCM through ferroptosis modulation. The formulation composition, chemical structure, and possible targets or mechanisms presented here offer valuable insights into the advancement of TCM exploration.

Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related deaths among women worldwide. Great progress has been recently achieved in controlling breast cancer; however, mortality from breast cancer remains a substantial challenge, and new treatment mechanisms are being actively sought. Programmed cell death (PCD) is associated with the progression and treatment of many types of human cancers. PCD can be divided into multiple pathways including autophagy, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis, and anoikis. Ubiquitination is a post-translational modification process in which ubiquitin, a 76-amino acid protein, is coupled to the lysine residues of other proteins. Ubiquitination is involved in many physiological events and promotes cancer development and progression. This review elaborates the role of ubiquitin-specific protease (USP) in programmed cell death, which is common in breast cancer cells, and lays the foundation for tumor diagnosis and targeted therapy.

As living standards elevate, cancers are appearing in growing numbers among younger individuals globally and these risks escalate with advancing years. One of the reasons is that instability in the cancer genome reduces the effectiveness of conventional drug treatments and chemotherapy, compared with more targeted therapies. Previous research has discovered non-coding RNAs' crucial role in shaping genetic networks involved in cancer cell growth and invasion through their influence on messenger RNA production or protein binding. Additionally, the interaction between non-coding RNAs and oxidative stress, a crucial process in cancer advancement, cannot be overlooked. Essentially, oxidative stress results from the negative effects of radicals within the body and ties directly to cancer gene expression and signaling. Therefore, this review focuses on the mechanism between non-coding RNAs and oxidative stress in cancer progression, which is conducive to finding new cancer treatment strategies.

Post-translational modifications (PTMs) of proteins play a crucial role in living organisms, altering the properties and functions of proteins. There are over 450 known PTMs involved in various life activities. LSD1 (lysine-specific demethylase 1) is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4 (H3K4) and histone H3 lysine K9 (H3K9). This ability of LSD1 allows it to inhibit or activate transcription. LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of these PTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders, neurological disorders, cardiovascular diseases, and bone diseases. Understanding the species of PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvement in diverse physiological and pathological processes. In this review, we discuss the structural characteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes. Furthermore, we describe human diseases associated with abnormal expression of LSD1. This comprehensive analysis sheds light on the intricate interplay between PTMs and the functions of LSD1, highlighting their significance in health and diseases.

Exosomes, a type of extracellular vesicle, are commonly found in different body fluids and are rich in nucleic acids (circRNA, lncRNAs, miRNAs, mRNAs, tRNAs, etc.), proteins, and lipids. They are involved in intercellular communication. lncRNAs are responsible for the modulation of gene expression, thus affecting the pathological process of kidney injury. This review summarizes the latest knowledge on the roles of exosome lncRNAs and circulating lncRNAs in the pathogenesis, biomarker discovery, and treatment of chronic kidney disease, renal fibrosis, and acute kidney injury, providing an overview of novel regulatory approaches and lncRNA delivery systems.

The subventricular zone (SVZ) is a region surrounding the lateral ventricles that contains neural stem cells and neural progenitor cells, which can proliferate and differentiate into various neural and glial cells. SVZ cells play important roles in neurological diseases like neurodegeneration, neural injury, and glioblastoma multiforme. Investigating the anatomy, structure, composition, physiology, disease associations, and related mechanisms of SVZ is significant for neural stem cell therapy and treatment/prevention of neurological disorders. However, challenges remain regarding the mechanisms regulating SVZ cell proliferation, differentiation, and migration, delivering cells to damaged areas, and immune responses. In-depth studies of SVZ functions and related therapeutic developments may provide new insights and approaches for treating brain injuries and degenerative diseases, as well as a scientific basis for neural stem cell therapy. This review summarizes research findings on SVZ and neurological diseases to provide references for relevant therapies.

Transcription factor E74 like ETS transcription factor 4 (ELF4), a member of the ETS family, is highly expressed in normal human hematopoietic tissue, ovary, placenta, colon, and certain pathological cell lines. During normal physiological processes, ELF4 regulates differentiation in osteogenic, adipocyte, and neuronal types. It also exerts a critical impact on the development of the immune system. However, its function is dysregulated through posttranslational modifications, gene fusions, and complex signaling crosstalk under pathological conditions. Furthermore, serving as a double-edged sword in cancer, ELF4 exhibits both tumor-suppressing and tumor-promoting effects. Specifically, ELF4 plays a critical role in cancer metastasis, proliferation, and modulation of the tumor microenvironment. This review provides an in-depth overview of the molecular structure and post-translational modifications of ELF4. It also summarizes the hallmarks of ELF4 in physiology and diseases, with a particular focus on its significance in oncology. Notably, this review underscores the potential of ELF4 as a prognostic biomarker, highlighting its clinical relevance. Finally, it discusses unresolved questions and future research directions of ELF4. An in-depth understanding of ELF4 biology could facilitate its clinical translation and offer promising targeted therapeutic strategies.

Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a spectrum of liver diseases ranging from metabolic dysfunction-associated fatty liver to metabolic dysfunction-associated steatohepatitis, which may progress to liver cirrhosis and hepatocellular carcinoma. Several mechanisms, including obesity, insulin resistance, dyslipidemia, inflammation, apoptosis, mitochondrial dysfunction, and reactive oxygen species, have been proposed to underlie the progression of MAFLD. Transcription factors are proteins that specifically bind to DNA sequences to regulate the transcription of target genes. Numerous transcription factors regulate MAFLD by modulating the transcription of genes involved in steatosis, inflammation, apoptosis, and fibrosis. Here, we review the pathological factors associated with MAFLD, with a particular emphasis on the transcription factors that contribute to the progression of MAFLD and their therapeutic implications.

Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator that primarily inhibits downstream gene expression by tri-methylating histone H3, which is usually overexpressed in tumors and participates in many processes such as tumor occurrence and development, invasion, migration, drug resistance, and anti-tumor immunity as an oncogene, making it an important biomarker in cancer therapy. Collectively, several transcription factors and RNAs cooperate to facilitate the elevated expression of EZH2 in cancer. Although the significance of blocking EZH2 in cancer for inhibiting cancer progression is widely recognized, the clinical application of EZH2 inhibitors continues to encounter numerous challenges. In this review, drawing upon our comprehensive understanding of the factual underpinnings of EZH2's role in cancer, we aim to clarify the crucial importance of targeting EZH2 in cancer treatment. Furthermore, we summarize the current research landscape surrounding targeted EZH2 inhibitors and offer insights into potential future applications of these inhibitors.

tRNA-derived small RNAs (tsRNAs) are non-coding small RNAs that are produced through the precise cleavage of tRNA molecules under specific conditions. tsRNA has multiple functions, including inhibiting translation, acting in association with classical small RNA effector mechanisms, or acting in conjunction with Argonaute proteins that affect cell proliferation, migration, cycle, and apoptosis. Recent studies have revealed the clinical potential of tsRNAs in numerous diseases. This article aims to provide a comprehensive and up-to-date review of the classification and biological function of tsRNAs in gastrointestinal diseases. Furthermore, this review explores the underlying mechanisms by which tsRNAs are believed to exert their effects in both tumor and non-tumor digestive tract diseases. Therefore, specific tsRNAs prove promising for disease diagnosis, prognosis prediction, and therapeutic interventions as novel biomarkers for digestive tract diseases.

Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients' response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquire significant ICI response-associated cells. Candidate drugs were identified using a blend of various drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patients in both subtypes showed varying overall survival, immunity levels, biological activities, and TP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation with immune-promoting scores but a negative correlation with immune-suppressing scores. Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related natural killer cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cells and docetaxel may offer new hope for ICI treatment in HCC.

Hepatocyte proliferation is essential for recovering liver function after injury. In liver surgery, the mechanical stimulation induced by hemodynamic changes triggers vascular endothelial cells (VECs) to secrete large amounts of cytokines that enhance hepatocyte proliferation and play a pivotal role in liver regeneration (LR). Piezo1, a critical mechanosensory ion channel, can detect and convert mechanical forces into chemical signals, importing external stimuli into cells and triggering downstream biological effects. However, the precise role of Piezo1 in VECs, especially in terms of mediating LR, remains unclear. Here, we report on a potential mechanism by which early changes in hepatic portal hemodynamics activate Piezo1 in VECs to promote hepatocyte proliferation during the process of LR induced by portal vein ligation in rats. In this LR model, hepatocyte proliferation is mainly distributed in zone 1 and zone 2 of liver lobules at 24–48 h after surgery, while only a small number of Ki67-positive hepatocytes were observed in zone 3. Activation of Piezo1 promotes increased secretion of epiregulin and amphiregulin from VECs via the PKC/ERK1/2 axis, further activating epidermal growth factor receptor (EGFR) and ERK1/2 signals in hepatocytes and promoting proliferation. In the liver lobules, the expression of EGFR in hepatocytes of zone 1 and zone 2 is significantly higher than that in zone 3. The EGFR inhibitor gefitinib inhibits LR by suppressing the proliferation of hepatocytes in the middle zone. These data provide a theoretical basis for the regulation of LR through chemical signals mediated by mechanical stimulation.

Gliomas represent the most common primary malignant intracranial tumors in adults. Despite recent advances in treatment, the prognosis of patients with glioblastoma remains poor. Epigenetic abnormalities, the hallmarks of various types of cancer, contribute to the dysregulated expression of cancer-related genes. Post-translational modification of histones plays a pivotal role in cancer development and progression by modulating gene transcription, chromatin remodeling, and nuclear structure. Therefore, further exploration of the molecular mechanisms of epigenetic regulation in gliomas and the identification of superior therapeutic targets are required. High-mobility group nucleosomal-binding domain 2 (HMGN2) participates in the epigenetic regulation of genes through histone modification and exhibits significant differential expression between glioma and normal tissues. However, the effect of HMGN2 on gliomas and its underlying mechanisms remain unclear. This study aimed to elucidate these uncertainties by demonstrating that HMGN2 significantly promotes the proliferation of glioma cells. HMGN2 binds to histones and promotes the stability of H3K27ac acetylation in the cell division cycle 20 (CDC20) promoter region, enhancing the transcriptional activity of CDC20 and increasing the proliferation of glioma cells. Moreover, we found that CDC20 expression was negatively correlated with the survival time of patients with glioma. These results suggest that targeting epigenetic regulation, such as the HMGN2/CDC20 axis, may provide a novel direction for the treatment of gliomas.

Pulmonary fibrosis is a devastating lung disease without effective treatment options. Sphingosine-1-phosphate receptor 3 (S1pr3), a receptor for the lipid signaling molecule sphingosine-1-phosphate, has been shown to mediate the development of pulmonary fibrosis, although the underlying mechanism is not fully understood. Here, we found increased expression of S1pr3 in the lung during the process of bleomycin-induced pulmonary fibrosis in mice and specific overexpression of S1pr3 in the infiltrated M2 macrophages. We constructed LysM-Cre+/S1pr3flox/flox mice, in which S1pr3 was conditionally depleted in myeloid cells, and this depletion protected mice from bleomycin-induced lung injury and fibrosis, with reduced M2 macrophage accumulation in the lung. Increased S1pr3 expression was found in bone marrow-derived macrophages after alternatively activated by IL4 ex vivo, while loss of S1pr3 attenuated IL-4-induced M2 polarization in bone marrow-derived macrophages by repressing the PI3K/Akt-Stat3 signaling pathway. Moreover, the S1pr3 inhibitors CAY10444 and TY52156 exerted protective effects on pulmonary fibrosis in mice. Taken together, our research showed that inhibition of S1pr3 ameliorates bleomycin-induced pulmonary fibrosis by reducing macrophage M2 polarization via the PI3K/Akt-Stat3 signaling pathway, indicating that S1pr3 may be a potential target for pulmonary fibrosis treatment.

The pathogenesis of neuroblastoma with bone or bone marrow metastasis (NB-BBM) and its complex immune microenvironment remain poorly elucidated, hampering the advancement of effective risk prediction for BBM and limiting therapeutic strategies. Feature recognition of 142 paraffin-embedded hematoxylin-eosin-stained tumor section images was conducted using a Swin-Transformer for pathological histology to predict NB-BBM occurrence. Single-cell transcriptomics identified a tumor cell subpopulation (NB3) and two tumor-associated macrophage (TAM) subpopulations (SPP1+ TAMs and IGHM+ TAMs) closely associated with BBM and highlighted transketolase (TKT) as a key molecular marker for metastatic progression in NB. This extensive multi-omics investigation into NB-BBM enhances our understanding of single-cell transcriptional dynamics in NB beyond existing research, outlining the evolution from in situ carcinoma through tumorigenesis to bone marrow metastases. Furthermore, exploration of the immune microenvironment identified specific subpopulations of TAMs crucial in promoting NB-BBM, presenting new avenues for immunotherapy. These insights enhance our understanding of the metastatic process from NB to BBM and facilitate the development of more effective diagnostic and therapeutic strategies for this aggressive pediatric cancer.

Non-alcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome arising from lipid metabolic imbalance, with its prevalence increasing globally. In this study, we observed a significant up-regulation of interferon regulatory factor 8 (IRF8) in the liver of NAFLD model mice and patients. Overexpression of IRF8 induced lipid accumulation in the mouse primary hepatocytes. Mice with adeno-associated virus-mediated IRF8 overexpression exhibited hepatic steatosis due to up-regulated peroxisome proliferator-activated receptor γ (PPARγ) expression and increased fatty acid uptake and lipogenesis. In vitro, small interfering RNA-mediated IRF8 knockdown attenuated triglyceride accumulation by dampening PPARγ expression through transcriptional inhibition of brain and muscle ARNT-like 1. The PPARγ-specific antagonist GW9662 abolished the effect of IRF8 overexpression. Furthermore, adeno-associated virus-mediated IRF8 knockdown in the mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome. These findings indicate that IRF8 plays a vital role in modulating hepatic lipid metabolism in a PPARγ-dependent manner and provide a previously unknown insight into NAFLD therapeutic strategies.

Isoleucyl-tRNA synthetase 2 (IARS2), originally regarded as an enzyme ligating isoleucine to the corresponding tRNA, has been identified as an oncogene recently. However, its function in pancreatic ductal adenocarcinoma (PDAC) remains to be discovered. Here we explored the biological role of IARS2 in PDAC. Up-regulated IARS2 was found in PDAC tissues and cell lines. Kaplan–Meier survival analysis indicated a worse prognosis in patients with high IARS2 expression. CCK-8, EdU, and colony formation assays showed IARS2 overexpression enhanced PDAC proliferation, which was reduced by IARS2 knockdown. Meanwhile, IARS2 down-regulation inhibited PDAC metastasis by impeding epithelial–mesenchymal transition. These results were also supported by subcutaneous xenograft and metastasis assays in vivo. To figure out underlying mechanisms, differential and enrichment analyses were conducted and the WNT signaling pathway was discovered. Our results demonstrated that there was no significant relationship between the WNT signaling pathway key factor CTNNB1 and IARS2 at the transcription level. However, cycloheximide assays showed that IARS2 reduced the β-catenin degradation rate. IARS2 inhibited the phosphorylation of β-catenin at the Ser33/37 site and regulated downstream targets of WNT signaling including c-MYC, c-JUN, and MMP7. The enhancement of proliferation and metastasis caused by IARS2 could be reversed by MSAB, an agent that promotes β-catenin degradation. In summary, IARS2 facilitates PDAC proliferation and metastasis by stabilizing β-catenin, which leads to WNT/β-catenin activation. IARS2 serves as an underlying prognosis marker and a potential therapeutic target for PDAC.

Despite the availability of efficacious vaccines, COVID-19 persists and our knowledge of how SARS-CoV-2 infection affects host transcriptomics remains incomplete. Transcriptome analysis, which has progressed our understanding of the patient response to SARS-CoV-2 infection, can be enhanced by considering chimeric transcript expression. Here we assess and characterize chimeric RNAs found in the whole blood of 178 COVID-19 patients. STAR-Fusion, SOAPfuse, and EricScript were used to detect chimeric RNAs resulting in over 30,000 predictions with approximately 500 high-confidence predictions that were found by more than one software and filtered based on exon annotations around the chimeric splice junction. GO term enrichment performed on the 5′ and 3′ parental genes of chimeric RNAs found in severe and critical patients resulted in pathways known to be affected in these patients, such as erythroid differentiation. Motif enrichment analysis of sequences proximal to chimeric splice junctions found in COVID-19 patients versus those found in GTEx whole blood revealed two RNA binding proteins previously implicated with coronavirus infection, PTBP1 and SFPQ. We discovered a chimeric RNA that correlated with COVID-19 disease status and appeared to be dependent upon a loss of PTBP1's function as a splicing repressor. Overall, we found over 350 novel COVID-19-specific chimeric RNAs not detectable in GTEx whole blood that may also serve as biomarkers for viral infection.

Cystinuria is the most common inheritable cause of kidney stone disease, with males exhibiting a higher susceptibility than females. However, the cellular origin and underlying mechanisms of sex differences in cystinuria remain elusive. This study aims to investigate the mechanism using Slc3a1 knockout mice. We found that male mice lacking the Slc3a1 gene exhibited more severe stone formation and renal injuries, unaffected by double knockout of another sex-dependent-expressed cystine transporter Slc7a13 or orchidectomy procedure. Further investigations revealed aberrant mitochondrial functions as the primary factor contributing to the severity of cystinuria in Slc3a1 knockout male mice. Mechanistically, higher SLC3A1 levels in male kidneys could enhance mitochondrial functions through modulation of mitochondrial NAD+ uptake primarily in proximal tubule cells. Supplementation with an NAD+ precursor rescued the sex differences caused by Slc3a1 knockout. Our studies uncover the crucial role of Slc3a1 in mitochondrial functions and provide novel insights into potential interventions for sexual dimorphism of cystinuria.

Although bone morphogenetic protein 2 (BMP2) can induce chondrogenic differentiation of mesenchymal stem cells (MSCs), its induction of endochondral ossification limits the application of BMP2-based cartilage regeneration. Here, we clarified the mechanisms of BMP2-induced endochondral ossification of MSCs. In vitro and in vivo chondrogenic, osteogenic, and angiogenic differentiation models of MSCs were constructed. The expression of target genes was identified at both protein and mRNA levels. RNA sequencing, molecular docking, co-immunoprecipitation, and chromatin immunoprecipitation followed by sequencing were applied to investigate the molecular mechanisms. We found that BMP2 up-regulated the expression of Notch receptors and ligands in MSCs. Notch1 signaling activation was related to inhibition of chondrogenic differentiation, promotion of osteogenic and angiogenic differentiation. In vivo ectopic stem cell implantation identified that Notch1 signaling activation blocked BMP2-induced chondrogenesis and facilitated endochondral ossification of MSCs. Mechanistically, we elucidated Notch1 intracellular domain (NICD1)-RBPjk complex binding to SRY-box transcription factor 9 (Sox9) and vascular endothelial growth factor A (VEGFA) promoters to decrease Sox9 expression and increase VEGFA expression. These findings suggest that Notch1 signaling can regulate BMP2-induced endochondral ossification by promoting RBPjk-mediated Sox9 inactivation and VEGFA expression. It is conceivable that targeting Notch1 signaling mediated endochondral ossification would benefit BMP2-based cartilage regeneration.

X-linked severe combined immunodeficiency disease (X-SCID) is a rare inherited disease caused by mutations in the interleukin 2 receptor subunit gamma gene (IL2RG), which encodes the common γ chain protein, a subunit of the receptor for lymphocytes. X-SCID is characterized by profound defects in T-cell, B-cell, and natural killer cell function. Here, we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations. Among those, the two adolescent patients with an atypical immunotype were confirmed by further analyzing IL-2-JAK-STAT5 signaling, T cell proliferation, and T cell receptor excision circles (Trecs). Interestingly, Bacillus Calmette-Guérin (BCG) disease occurred commonly in this cohort. Although allogeneic hematopoietic stem-cell transplantation is curative for the disease, it is not available to all patients due to the lack of suitable matched donors. Autologous gene therapy using a self-inactivating lentiviral vector (SIN-LV) technology has provided an alternative therapy for such mono-genetic diseases. Here, we performed the pre-clinical studies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG and CD34+ stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID. This work is done complied with the established “Good Manufacturing Practice” (GMP) used in the clinical trials. In addition, a safety study is performed using the transduced CD34+ cells implanted into the axilla of nude mice in vivo. Overall, our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV, which paves the way for conducting X-SCID gene therapy clinical trials in China in the near future.

Bone morphogenetic protein 9 (BMP9) has remarkable potential to induce the differentiation of mesenchymal stem cells (MSCs) towards the osteoblastic lineage. Additionally, research suggests that certain growth factors have the ability to potentiate BMP9-induced osteogenic differentiation of MSCs. Sonic Hedgehog (Shh) plays an indispensable role in the regulation of skeletal development. The objective of this research was to assess the potential influence of Shh on BMP9-induced osteogenic differentiation of MSCs. Our findings indicated that Shh effectively enhanced BMP9-induced early and late osteogenic differentiation of MSCs, and increased BMP9-induced expression/transcriptional activity of osteogenesis-related transcription factors. Besides, it was observed that Shh promoted BMP9-induced ectopic bone formation of MSCs in vivo. Moreover, BMP9 was able to facilitate the repair of bone defects in rats, while Shh further accelerated this reparative process. Mechanistically, Shh enhanced the activation of the Smad1/5/8 signaling pathway which was induced by BMP9. Furthermore, GANT-61, an inhibitor of Gli1 and Gli2, attenuated the enhancing effect of Shh on BMP9-induced osteogenic differentiation of MSCs. Collectively, the co-administration of BMP9 and Shh may present a promising therapeutic approach for the treatment of fracture nonunion, delayed fracture healing, and bone defects.

SPP1+ macrophages have been identified as key players in the colorectal cancer (CRC) tumor microenvironment, but their function remains unclear. This study integrated single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of SPP1+ macrophages in CRC. Our findings revealed a pronounced elevation of SPP1+ macrophages in CRC, especially within tumor territories. These macrophages served as markers for CRC initiation, progression, metastasis, and potential prognosis. Furthermore, they showed heightened transcriptional activity in genes linked to angiogenesis, epithelial–mesenchymal transition, glycolysis, hypoxia, and immunosuppression. SPP1 protein amplified CRC cell migration and invasion, potentially mediating cellular crosstalk via the SPP1-CD44, SPP1-PTGER4, and SPP1-a4b1 complex axes. Patients with a high proportion of SPP1+ macrophages could benefit more from immune checkpoint blockade therapy. Interestingly, CSF1R expression was significantly enriched in C1QC+ macrophages versus SPP1+ macrophages, possibly explaining limited anti-CSF1R monotherapy effects. In conclusion, we propose an SPP1+ macrophage model in CRC, highlighting such macrophages as a promising therapeutic target due to their malignancy markers.

Iridocorneal endothelial (ICE) syndrome is a rare, irreversibly blinding eye disease with an unknown etiology. Understanding its genomic and epigenomic landscape could aid in developing etiology-based therapies. In this study, we recruited 99 ICE patients and performed whole-genome sequencing (WGS) on 51 and genome-wide DNA methylation profiling on 48 of them. We conducted mutational burden testing on genes and noncoding regulatory regions, comparing the ICE cohort with control groups (9197 East Asians from the gnomAD database and 350 normal Chinese from our in-house cohort). Copy number variation (CNV) analysis and differential methylation of regions were also explored. We identified RP1L1 (27/51, 53%) with a significantly higher coding-altering mutational burden in the ICE cohort (p < 8.3×10−7), with mutations predominantly at chr8:10467637 (hg19). Additionally, 41 regions with significant CNVs were identified, including two regions at chr19:15783859-15791329 (hg19) and chr3:75786061-75790887 (hg19), showing copy number loss in 39 and 19 patients, respectively. We also identified 2,717 differentially methylated regions (DMRs), with hypomethylation prevalent in ICE syndrome (91.9% of DMRs). Among these, 45 recurrent hypomethylated regions (HMRs) in more than 10% of ICE patients showed differential methylation compared to normal controls. This study presents the first comprehensive genomic and epigenomic characterization of ICE syndrome, offering insights into its underlying etiology.

Pancreatic ductal adenocarcinoma (PDAC) stands as a formidable malignancy characterized by its profound lethality. The comprehensive analysis of the transcriptional landscape holds immense significance in understanding PDAC development and exploring novel treatment strategies. However, due to the firm consistency of pancreatic cancer samples, the dissociation of single cells and subsequent sequencing can be challenging. Here, we performed single-cell RNA sequencing (scRNA-seq) on 8 PDAC patients with different lymph node metastasis status. We first identified the crucial role of MMP1 in the transition from normal pancreatic cells to cancer cells. The knockdown of MMP1 in pancreatic cancer cell lines decreased the expression of ductal markers such as SOX9 while the overexpression of MMP1 in hTERT-HPNE increased the expression of ductal markers, suggesting its function of maintaining ductal identity. Secondly, we found a S100A2+ tumor subset which fueled lymph node metastasis in PDAC. The knockdown of S100A2 significantly reduced the motility of pancreatic cancer cell lines in both wound healing and transwell migration assays. While overexpression of S100A2 led to increased migratory capability. Moreover, overexpression of S100A2 in KPC1199, a mouse pancreatic cancer cell line, caused a larger tumor burden in a hemi-spleen injection model of liver metastasis. In addition, epithelial-mesenchymal transition-related genes were decreased by S100A2 knockdown revealed by bulk RNA sequencing. We also identified several pivotal contributors to the pro-tumor microenvironment, notably OMD+ fibroblast and CCL2+ macrophage. As a result, our study provides valuable insights for early detection of PDAC and promising therapeutic targets for combatting lymph node metastasis.

Severe immune responses regulate the various clinical hepatic injuries, including autoimmune hepatitis and acute viral hepatitis. N6-methyladenosine (m6A) modification is a crucial regulator of immunity and inflammation. However, the precise role of YTHDF1 in T cell-mediated hepatitis remains incompletely characterized. To address this, we utilized Concanavalin A (ConA)-induced mouse liver damage as an experimental model for T cell-mediated hepatitis. Our findings found that hepatic YTHDF1 protein rapidly decreased during ConA-induced hepatitis, and YTHDF1-deficient (Ythdf1−/−) mice showed more susceptibility to ConA-induced liver injury, along with an intensified inflammatory storm accompanied by aggravated hepatic inflammatory response via ERK and NF-κB pathways. Interestingly, hepatic-specific over-expression or deletion of YTHDF1 exhibited redundancy in ConA-induced liver injury. Validation in bone marrow chimeric mice confirmed the necessity of YTHDF1 in hematopoietic cells for controlling the response to ConA-induced hepatitis. Additionally, our data revealed that YTHDF1 deletion in macrophages exacerbated the inflammatory response induced by lipopolysaccharide. In summary, our study uncovered that YTHDF1 deficiency exacerbates the immune response in ConA-induced hepatitis by modulating the expression of inflammatory mediators, highlighting the potential of YTHDF1 as a therapeutic target for clinical hepatitis.