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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Colorectal cancer (CRC) continues to be the third most frequently diagnosed cancer, and the second leading cause of cancer-related mortality. Several non-invasive biomarkers have emerged, but only a few have been incorporated into clinical practice due to the lack of sensitivity.1 Research on the epigenome has unveiled potential clinical applications for diagnosis and therapy response.2,3 Particularly, recent evidence suggests a novel role of RNA methylation in the development of CRC,4 revealing an overall RNA m6A hypomethylation.5 However, our understanding of their contribution to CRC remains limited. To address this, we investigated m6A modification in CRC using an integrative approach. High-throughput sequencing was performed to analyze the m6A-epitranscriptome (methylated RNA immunoprecipitation sequencing; m6A), transcriptome (mRNA), and alternative splicing events (AS; RNA sequencing) in leukocytes from both healthy participants (n = 16) and patients with CRC (n = 15) (Table S1 summarizes the baseline characteristics of the participants) from the “Virgen de la Victoria” University Hospital, Málaga, Spain.

CRISPR/Cas9 is a versatile genome editing tool that has the potential to be used to cure many genetic diseases. The system works via a guide RNA (gRNA) interacting with the Cas9 protein to form a complex that binds to a specific DNA sequence.1 The site-specific DNA binding feature of the Cas9 system can be utilized in a variety of ways to correct gene mutations or to regulate gene expression. First, the Cas9 protein can make a site-specific double-stranded break that is mainly repaired by homology-directed repair or non-homologous end-joining. Both pathways can be used for gene editing or gene insertion when proper donor DNA is present.1 Second, the Cas protein can be modified into a nickase, which creates a site-specific nick. When fused with other proteins, such as adenosine deaminase, cytosine deaminase, or reverse transcriptase, the modified Cas9 protein can be used for base editing2 or prime editing.3 While cytosine base editors and adenine base editors allow single-nucleotide changes at target sites specified by the gRNA, prime editors, with the gRNA modified to include a template sequence for reverse transcription, can offer single nucleotide substitution as well as short deletions or insertions.3 The recently improved prime editing systems include three gRNAs: an engineered pegRNA (epegRNA) to locate the target site for initiation of the prime editing, a nicking gRNA to nick the unedited DNA strand to enhance the editing efficiency, and a dead single gRNA (dsgRNA) to recruit the Cas9 protein near the editing site to enhance editing efficiency.3 In addition, the Cas9 protein can be fused with a transposase, such as in the Find and Cut-and-Transfer (FiCAT) system, to perform site-specific gene integration.4 Finally, a modified Cas9 protein can serve as a site-specific DNA binding protein to regulate gene transcription by fusing with a transcription activator or inhibitory motif. In all the above gene editing or gene regulation approaches using Cas9, proper levels of gRNA presence are essential for targeting efficiency. In the case of prime editing, even the ratio of gRNA expression is critical; the epegRNA level should be at least three-fold higher than the nicking gRNA or dsgRNA.3 Currently, there is no reliable, convenient method to precisely measure levels of gRNA expression. In this study, we developed a rapid, sensitive, cost-effective, and non-radioactive method for gRNA detection.

A growing body of evidences suggests that mesenchymal stroma cells (MSCs) are not only a therapeutic resource to treat various diseases, but also an important pathogenic worker in tumorigenesis.1 However, the differences between in vitro and in vivo environment draw the major concern leading to the contradictory effects of MSCs on tumorigenesis.2 Technical limitation makes it even hard to dissect the real cell–cell interacting model in a living status. As like a two-edge sword, dissecting the underlying mechanism resulting in this dilemma would help to apply MSCs more accurately in translational medicine. In our study, we applied murine in vivo calvarium intravital microscopy (IVM) and in vivo flow cytometry (IVFC) to directly observe the dynamic cell–cell interaction between acute lymphoblastic leukemia cells (L1210s) and BM (bone marrow)-MSCs. Our data clarified a living model by which BM-MSCs provide a micro-niche to facilitate leukemia cells invasion.

Osteoarthritis (OA) is the most common joint disease in elderly patients. Its main pathological change is articular cartilage degeneration, accompanied by synovial inflammation and changes in subchondral bone structure, resulting in pain and limited mobility. However, previous studies on OA mainly focused on the dysfunction of cartilage and chondrocytes, and the synovium and other joint structures have not received enough attention. Synovium has shown inflammatory changes to varying degrees before the morphological changes of articular cartilage occur in the early stage.1 Synovial fibroblasts are the most important cell type in the synovium of arthritic hyperplasia. A large number of studies have shown that fibroblasts in synovium participate in the activities of arthritis, but the specific molecular mechanism is still unclear.2 Ferroptosis refers to a new type of cell death caused by the abnormal accumulation of iron-dependent reactive oxygen species, which leads to the imbalance of oxidation and reduction. Zhu et al found that by activating the ferroptosis pathway, ferroptosis can reduce the number of synovial fibroblasts in the mouse arthritis model, thereby inhibiting the damage to articular cartilage and delaying the progress of arthritis.3 Therefore, the ferroptosis pathway targeting synovial fibroblasts can provide a new therapeutic strategy for OA and better study its molecular mechanism.

Circular RNAs (circRNAs) are endogenous RNAs formed by back-splicing1 and possess a more stable molecular structure.2 circRHOT1 promotes HCC progression by inducing nuclear receptor subfamily 2 group F member 6 (NR2F6) expression3 and m6A-mediated up-regulation of circMDK and circSTX6 facilitates tumorigenesis.4 Wang et al revealed that circTGFBR2 was a novel tumor promoter circRNA and promoted HCC progression.5 However, the role and molecular mechanism of circ-miR-524 in hepatocarcinogenesis have been poorly elucidated. In this study, we clearly demonstrate that circ-miR-524 accelerates the growth of liver cancer cells by altering transcriptome, proteome, and DNA damage repair. In particular, circ-miR-524 enhances the expression of K-RAS, which determines the carcinogenic function of miR-circ-524. These results provide a basis for research on liver cancer prevention, diagnosis, and treatment.

CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) has been reported to suppress tumors significantly in various cancer types. However, the molecular biological functions of CMTM3 outside of cancer remain largely unknown. In our study, we aim to discover novel functions of CMTM3 in adipocytes and elucidate the molecular mechanism through which CMTM3 functions in adipogenesis. We observed a significant positive role of CMTM3 during adipocyte differentiation in both gain- and loss-of-function experiments. Mechanically, co-immunoprecipitation and luciferase assay were applied to confirm the relationship between peroxisome proliferator-activated receptor gamma (PPARγ) and CMTM3. Furthermore, the functional study of CMTM3 mutations facilitated our understanding of the regulation of adipogenesis. Our findings reveal a new biological function of CMTM3 in adipogenesis and shed light on its potential as a molecular target in obesity therapy.

The myostatin (MSTN) gene, also known as growth and differentiation factor 8 (GDF8), plays a critical role in regulating muscle mass in animals by negatively controlling the number and size of skeletal myocytes. MSTN mutations have been demonstrated to cause the double-muscling (DBM) phenomenon in various species, including cattle, sheep, mice, pigs, dogs, rabbits, and even humans.1 In this study, we explored the evolutionary characteristics, biochemical structure and function impacts of the sheep MSTN gene (oMSTN) using phylogenetic analysis, mutation effect evaluation, residue conservation studies, structural modeling, and protein–protein docking. Our findings suggest that the evolutionary characteristics and biochemical structural features of oMSTN are closely tied to its functional and clinical roles in regulating skeletal muscle growth. We validated our hypothesis by creating MSTN gene-edited sheep using CRISPR/Cas9 technology. These results provide valuable insights for the preparation of animal models and the rapid and effective improvement of meat production. Furthermore, evaluating the effects of MSTN inhibition in animal models with diverse human diseases could support the development of MSTN inhibitors for future clinical applications.

Hereditary disorders often present remarkable genetic and clinical heterogeneities, but bridging the gap between pathogenic mutation and clinical consequences remains challenging. One plausible explanation is the presence of second-hit modifier mutations, which could create additional genetic complexity to contribute to clinical heterogeneities. We propose to trace modifier mutations by focusing on single-pedigree patients who present divergent clinical phenotypes; this scenario would ensure shared pathogenic mutations and highly related genetic makeups, thus simplifying the detection of second-hit modifiers. An appropriate window to test this idea lies in the case of low-density lipoprotein receptor-related protein 6 (LRP6), which encodes one essential co-receptor of Wnt signaling and is involved in multiple human diseases. In particular, LRP6 has been discovered as a frequent pathogenic gene for tooth agenesis (absence of one or more permanent teeth) or in rare cases for ectodermal dysplasia where affected members showed variable abnormalities of teeth, hair, and sweat glands.1 Yet the pathogenic mechanism of LRP6-related tooth agenesis and the genetic cause for its clinical heterogeneity remain unclear. Here, we report a novel LRP6 C1032F mutation in one ectodermal dysplasia family, highlighting YWTD-motif targeting as a generalized mechanism in LRP6-associated tooth agenesis and involvement of second-hit modifier mutations in LRP6-associated clinical heterogeneity.

Chromosomal instability (CIN) drives cancer development by causing the accumulation of significant gains, losses, and rearrangements of DNA, although the degree to which this impact relies on DNA damage is uncertain in terms of mechanisms and key molecules. Nevertheless, a structured system for evaluating various forms of CIN and their impact on hepatocellular carcinoma (HCC) is lacking. Here we evaluated CIN as a hallmark of HCC with LASSO risk prognostic model. Our framework figured out that DNA polymerase theta (POLQ) facilitated CIN in HCC and exhibited higher levels of expression in HCC compared with normal tissues. Moreover, the increased POLQ expression was closely linked to the poor prognosis of patients with HCC. This biomarker indicates a negative outlook, worsening the irregularities in spindle formation, chromosomes, and chromosome bridges, elevating the protein levels of key spindle assembly checkpoint components, and promoting the cell cycle and proliferation of HCC cells. Our results demonstrate an excellent diagnostic model in distinguishing CIN in HCC, and the POLQ promoted CIN and could guide the clinical diagnosis, prognosis, and therapy in HCC. The findings could offer fresh perspectives on tailored therapy for HCC and improve the prognosis of HCC patients.

Familial hypercholesterolemia is an autosomal dominant disorder characterized by a significant elevation of total cholesterol, especially low-density lipoprotein cholesterol (LDL-C).1 Mutations in the function of both LDL receptor (LDLR) and proprotein convertase subtilisin kexin 9 (PCSK9) genes are responsible for familial hypercholesterolemia.2 It is not yet clear whether the simultaneous intervention of both genes can have a synergistic effect on achieving further lipid-lowering goals. We investigated whether dual-target intervention could further reduce lipid levels and achieve improved therapeutic outcomes using adeno-associated virus (AAV) to overexpress the LDLR gene and by simultaneously performing knocking of the PCSK9 gene.

Neurodevelopmental disorders such as autism spectrum disorder (ASD), are complex conditions influenced by both genetic and environmental factors. Epigenetic changes serve as a critical bridge between these factors, potentially mediating the effects of environmental exposures on gene expression patterns crucial for neural development. These modifications, occurring during pregnancy or early postnatal life, could have long-term effects on genes associated with neurodevelopment, increasing the risk of neurodevelopmental disorders. Valproic acid (VPA) is linked to an increased risk of ASD when exposure occurs in utero.1 VPA-exposed rodent models accurately reflect human ASD conditions, demonstrating changes in social behaviors and glial precursor proliferation that may influence synaptic connectivity, neuroinflammation, and the integrity of the blood–brain barrier, all of which are implicated in ASD pathophysiology.2 VPA inhibits histone deacetylase, leading to histone acetylation (e.g., H3K27ac) and affecting the epigenetic regulation of genes involved in neurogenesis and transcription factors such as Ascl13 and Foxo3.4 This study investigates epigenetic mechanisms, including histone modification and DNA methylation, impacting brain development in neonatally VPA-exposed rats.

Neurofibromin 2 (NF2)-related schwannomatosis (NF2-SWN) is an autosomal-dominant tumor predisposition syndrome. NF2-SWN patients develop multiple benign tumors of the nervous system, such as schwannomas, particularly bilateral vestibular schwannomas, without current effective treatments.1 These tumors are caused by the bi-allelic inactivation of the NF2 gene, which encodes for merlin protein, in a cell of the Schwann cell (SC) lineage.2 Changes in merlin result in the dysregulation of a wide variety of signaling cascades from the cell surface to the nucleus, such as the Hippo signaling pathway, by repressing YAP/TAZ nuclear translocation, and the FAK and PI3K/AKT/mTOR, Ras/Raf/MAPK, TP53, and Rac1-Pak1 pathways.3

Cases of inherited retinal dystrophy (IRD) can be caused by mutations in the MERTK gene, which results in an autosomal recessive form of blindness (retinitis pigmentosa, RP) characterized by impaired phagocytosis of photoreceptor outer segments (POS) by retinal pigment epithelial cells (RPE). Persistent MERTK gene mutations in patient-derived human induced pluripotent stem cells (hiPSCs) pose a challenge for autologous stem cell-derived RPE replacement therapies targeting IRD. In a previous study, we created a hiPSC-based disease model of early-onset RP caused by a mutation in the human MERTK gene (homozygous frameshift mutation c.992_993delCA(p.Ser331Cysfs∗5)).1 The hiPSC patient's derived RPE showed impaired POS phagocytosis.1 Applying CRISPR/Cas9 gene-editing technology supported the generation of heterozygously and homozygously corrected RP-hiPSC lines, RP1-FiPS4F1-GC1 and RP1-FiPS4F1-GC2, respectively.2 The RPE cells derived from these isogenic hiPSC recovered both wild-type MERTK protein expression and recovered the function of phagocytosis of POS.

Long noncoding RNAs (lncRNAs), especially angiogenesis-related lncRNAs (ARLncs), are vital cancer biomarkers.1,2 This study explores their role in lung adenocarcinoma (LUAD), focusing on their influence on the tumor environment and angiogenesis. We identified 12 ARLncs to develop a prognostic signature independent of conventional indicators for LUAD patients. Notably, the low-risk group showed better outcomes, higher cytotoxic T-lymphocyte-associated protein 4 (CTLA4) expression, and improved response to CTLA4 checkpoint inhibitors. LINC00892 stood out as a key regulator of CTLA4 expression, linked to increased levels via vascular endothelial growth factor A (VEGFA). LINC00892 overexpression in LUAD cells boosted human umbilical vein endothelial cell (HUVEC) proliferation and migration by sponging miR-130b-3p and controlling VEGFA. This study introduces an innovative ARLncs-based prognostic model for LUAD, highlighting LINC00892's role in modulating CTLA4 expression through VEGFA, potentially guiding immunotherapy strategies for LUAD.

SPAG1 (sperm-associated antigen 1) is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia (PCD; OMIM244400), an inherited disorder affecting the function of motile cilia,1 highly conserved organelles protruding from the surface of eukaryotic cells. Pathogenic SPAG1 variants impair the assembly of dynein arms, essential elements of cilia. In a cohort of almost 300 affected individuals with the genetic bases of PCD explained during our long-term studies, pathogenic variants in SPAG1 were found in 60 unrelated patients, making it one of the most frequently involved genes in the Polish PCD population. Two predominant, previously reported variants1,2 were a nonsense mutation c.2014C>T in exon 16, found in both homozygotes and in compound heterozygotes, and a large 11,973 bp deletion encompassing parts of SPAG1, and of the upstream POLR2K (RNA polymerase II, I and III subunit K). c.2014C>T was found in 27 homozygotes and 31 compound heterozygotes, of whom 28 had the large deletion as the second allele; the large deletion was found in two more compound heterozygotes, accompanied in trans by rare pathogenic variants (Fig. 1A and Tables S1 and 2). Similar to previous reports,1,2 the large deletion was repetitively found in compound heterozygosity, but no homozygotes were identified.

Koolen-de Vries syndrome (KdVS, OMIM #610443) is a neurodevelopmental disorder characterized by distinctive facial characteristics, intellectual disability, and friendly behavior. A full KdVS phenotype can be caused by a recurrent 17q21.31 deletion of 0.3–0.6 Mb, as observed in about 70%–80% of cases, or by predicted truncating variants (PTVs) in KANSL1 (KAT8 regulatory NSL complex subunit 1) in the remaining 20%–30% of patients.1,2 PTVs were reported to affect any coding exon of the gene from 2 to 15 in typical KdVS patients. However, polymorphic duplications including exons 1–3 of KANSL1 (NM_015443.4) can make the final diagnosis of KdVS challenging (Suppl.Notes).3 Since certain PTVs in the first three exons of KANSL1 were described either as pathogenic or benign, likely depending on whether they affect the functional or the polymorphic copy of the gene, a gene-specific strategy for validation is needed.

As the first-generation tyrosine kinase inhibitor for epidermal growth factor receptor (EGFR-TKI), gefitinib has been proven effective for patients with Del19 or L858R mutations in EGFR. Secondary mutations in EGFR (mainly T790M) confer resistance to gefitinib in ∼50% of patients.1 However, resistance still occurs in other patients without secondary mutations in EGFR, which indicates that EGFR-independent mechanisms also play a vital role in the gefitinib resistance cascade, which deserves further investigation. Our previous studies have demonstrated that aldo-keto reductase 1C1 (AKR1C1) promotes non-small cell lung cancer (NSCLC) metastasis by directly interacting with signal transducer and activator of transcription-3 (STAT3) and reinforcing its activity.2 Although studies have focused on the protumor roles of AKR1C1, the role of AKR1C1 in gefitinib resistance is still unknown.

The loss of a pregnancy, including ectopic pregnancy (EP) and early pregnancy loss (EPL), significantly impacts women’s quality of life. Unfortunately, definitive causes can be identified in less than half of EP and EPL cases, presenting a substantial challenge for clinical treatment. Previous studies have revealed a significant relationship between the history of EPL and the increased risk of EP.1 Nevertheless, the interplay between EPL and EP remains unclear, highlighting the need to discover novel biomarkers to guide personalized treatment and clinical management. In response, we aim to investigate the underlying genetic interactions in EPL and EP. Using various bioinformatics analyses, we examined the genetic interactions of differentially expressed genes (DEGs) through RNA sequencing according to the workflow (Fig. S1).

There is growing evidence that acute hypoxia can be hazardous to health by causing damage to a variety of human organs. Gastrointestinal dysfunction is a common symptom of acute mountain sickness, and the pathogenesis of acute hypoxic gastrointestinal injury is complex. Additionally, the incidence of gastrointestinal disorders in people travelling to highland areas increases with altitude.1 Studies have shown that tryptophan possesses stress-relieving effects, but the specific effects and mechanisms of tryptophan require further elucidation. In this study, we analyzed the potential mechanism of tryptophan in ameliorating hypoxic intestinal stress injury under the induction of acute hypoxic stress using scanning electron microscopy, 16S rDNA sequencing, and gas chromatography. Our results showed that tryptophan supplementation could promote the recovery of the intestinal barrier, reduce intestinal permeability, and increase the species diversity of gut microbiota. Furthermore, it promoted the growth of beneficial bacteria and the production of their functional metabolites, short-chain fatty acids, in hypoxic stress mice. This could effectively alleviate hypoxia-induced intestinal injury and improve intestinal health.

Early diagnosis and effective treatment of hepatocellular carcinoma (HCC) are crucial. Hepatocarcinogenesis involves multiple genes and processes with complicated mechanisms. Recently, zinc finger proteins (ZNFs) have been found to constitute the largest family in the human genome and are functional proteins involved in regulating cell differentiation, embryonic development, and a variety of diseases. Additionally, the regulation of target gene transcription factors can vary with environmental stimuli and cell type. Complex ZNFs with up to 13 Krüppel-like transcription factor (KLF) abnormalities are related to the progression of multiple types of tumors. Here, we report a new molecular marker, KLF5. The up-regulated KLF5 mRNAs in human HCC tissues were confirmed via The Cancer Genome Atlas (TCGA) database, and abnormally increased KLF5 was analyzed in human HCC tissues via multicolor immunofluorescence technology. Additionally, the clinicopathological features of patients with KLF5 overexpression were TNM stage, tumor size, alpha fetoprotein (AFP) level, portal vein thrombosis, and HBV infection. High KLF5 expression was negatively correlated with the prognosis of HCC patients. Clinically, increased circulating KLF5 levels might be helpful in HCC diagnosis or differential diagnosis from patients with benign and malignant liver diseases. Mechanistically, KLF5 could be co-expressed with Wnt3a in the same HCC cells and might promote HCC progression via cross-talk.

Welander distal myopathy (WDM) is a rare autosomal dominant inherited muscular dystrophy.1 WDM patients share an unusual haplotype on chromosome 2p13, where a heterozygous missense founder mutation (c.1362G > A; p.E384K; substitution of glutamic acid for lysine in the protein) has been identified in TIA1, an RNA-binding protein and a core component of stress granules (SGs).2 SGs are stress-induced non-membranous cytoplasmic aggregates from proteins and RNAs.3 The effects of the WDM-TIA1 mutation have been associated with abnormalities in the dynamics of TIA1-dependent SGs.2 Although its genetic cause is known, WDM is poorly understood. Understanding the WDM-associated molecular mechanisms, particularly the alterations in cellular homeostasis, is essential to identify therapeutic opportunities. Here, we sought to elucidate the molecular and cellular defects associated with mutant TIA1 expression, which may be partly responsible for the deficiencies observed in WDM patients.

Dysregulation of cell cycle control plays a pivotal role in tumor progression. Acting as a crucial regulator of the G1/S phase transition, dysregulation of cyclin D1 (CCND1) can disrupt the delicate balance between cell proliferation and quiescence, leading to uncontrolled cell cycle progression.1 Endoplasmic reticulum stress influences the cell cycle through myriad pathways. During endoplasmic reticulum stress, the inositol-requiring enzyme 1 alpha (IRE1α) can be activated, and its endoribonuclease domain cleaves unspliced X-box binding protein 1 (XBP1u) mRNA, generating a spliced XBP1 (XBP1s) and a non-coding RNA, whose length is 26 nt (named exosomal 26-nt-long ncRNA, X26nt).2,3 Studies have demonstrated that XBP1s can induce the expression of pro-angiogenic factors, promoting the formation of new blood vessels.4,5 Our previous study demonstrated that gastric cancer exosome-derived X26nt induces tumor-associated angiogenesis via promoting endothelial cell migration targeting vascular endothelial-cadherin.2 However, the exact mechanisms by which XBP1 splicing regulates endothelial cell proliferation are still not fully understood.

A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2) is a member of the ADAMTS zinc metalloproteinase family, best known for its role as a procollagen I N-proteinase in the maturation of fibrillar collagens. Biallelic defects in the ADAMTS2 gene, resulting in a loss of ADAMTS2 enzyme activity and consequent retention of N-propeptides in type I procollagen molecules, lead to the rare monogenic disease Ehlers-Danlos syndrome dermatosparaxis type (dEDS) in humans, and dermatosparaxis in animals, conditions that are hallmarked by extreme fragility of the skin and other soft connective tissues. Recent studies have expanded the substrate repertoire of ADAMTS2 considerably, revealing its potential implication in several biological processes, including angiogenesis, lymphangiogenesis, neurodevelopment, immunity, and spermatogenesis. There is also emerging evidence for a role for ADAMTS2 in complex disorders, including cancer and cardiovascular and neurodegenerative disease. These findings may not only provide answers to hitherto unsolved questions in dermatosparaxis but also unveil a therapeutic and/or biomarker potential of ADAMTS2 in many diseases. This narrative review provides an in-depth overview of the discovery, structure, regulation, and enzymatic role of ADAMTS2, its role in fibrillar collagen maturation and in dEDS pathogenesis, as well as its newly discovered substrates and its potential role in complex disorders.

The circadian rhythm, a 24-h cycle, plays a crucial role in regulating gut physiological processes, particularly the proliferation and differentiation of intestinal epithelial cells, which are essential for gut homeostasis and repair. This review discusses the complex interactions between circadian rhythms, cell cycle regulation, and key signaling pathways (Wnt, Notch, and Hippo) in the context of the intestinal stem cell niche and epithelial cell fate decisions. Key molecules such as brain and muscle ARNT-like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), hairy and enhancer of split 1 (Hes1), and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) coordinate stem cell functions with circadian rhythms. We discuss how Notch signaling regulates the cell cycle and interacts with circadian rhythms. Additionally, we explore the role of Hippo-Wnt signaling in balancing cell proliferation and differentiation. Furthermore, we highlight the intricate relationships between circadian clock components and signaling pathways, emphasizing the importance of temporal coordination in determining epithelial cell fate. We also discuss shared enzymes, including casein kinase 1 delta (CK1δ), glycogen synthase kinase 3 (GSK3), and AMP-activated protein kinase (AMPK), which play a role in regulating the cell cycle, circadian rhythm, and signaling pathways. In summary, this review offers valuable insights into the regulatory mechanisms that control stem cell behavior and epithelial cell differentiation, suggesting promising directions for future research in intestinal biology and tissue homeostasis.

Decreased cardiac output in heart failure leads to intestinal ischemia and increased permeability. Substantial changes occur in the gut microbiota, characterized by a decline in beneficial bacteria and an overgrowth of potentially harmful bacteria. The gut microbiota is intricately linked to prevalent risk factors for heart failure, including hypertension, diabetes, obesity, and renal insufficiency. Furthermore, imbalanced microbiota-derived metabolites enter the bloodstream and may contribute to the progression of heart failure. Ongoing research explores gut microbiota manipulation to alleviate heart failure with probiotics, targeted antibiotics, fecal microbiota transplantation, and dietary adjustments. This review summarizes how gut microbiota participates in heart failure and highlights the emerging promise of modulating gut dysbiosis as a therapeutic approach for managing heart failure.

SET domain-containing 2 (SETD2) is a methyltransferase that catalyzes trimethylation of lysine 36 on H3 (H3K36me3) in mammals, an epigenetic mark associated with actively transcribed regions. SETD2 is implicated in multiple chromatin biological processes, such as alternative splicing, transcriptional regulation, DNA damage repair, and maintenance of genomic integrity. Extensive studies have demonstrated that SETD2-inactivating mutations and resultant dysregulation of these functions may result in tumorigenesis. However, the role of SETD2 in the development and function of immune cells receives relatively limited attention. In this review, we seek to summarize current knowledge of the biological function and underlying mechanisms of SETD2 and highlight its important role in immune cell biology. By influencing the biological processes of immune cells, SETD2 participates in the pathogenesis of immune-related diseases, including infection, cancers, autoimmune diseases, and inflammatory diseases. Finally, we discuss challenges and prospects for targeting SETD2 in immune cells to provide guidance for treating those diseases in clinical practice.

A hallmark feature of cancer is its capacity to induce the development of new blood vessels. Anti-angiogenic therapies are commonly employed to combat various types of cancer. Despite notable advancements in this field, limited efficacy and resistance remain critical challenges. While anti-angiogenic therapy primarily targets endothelial cells within the abnormal vasculature, the origins of tumor vascular endothelial cells in solid tumors remain a subject of ongoing debate. Unraveling the origins of these endothelial cells is crucial for developing more effective strategies to combat tumor angiogenesis. This review summarizes the latest findings on the origins of endothelial cells in tumor angiogenesis and explores the progress, limitations, and future directions of anti-angiogenic therapy.

Fucosylation is a post-translational modification that attaches fucose to glycoproteins or glycolipids, thereby influencing their biological functions. Consequently, fucosylation proves indispensable for many biological processes, such as ligand–receptor interaction, cell adhesion, and signal transduction, holding critical clinical significance in the genesis and development of diseases. Recent studies further unveiled the clinical significance and molecular mechanism underlying the pathogenetic role of aberrant fucosylation. Herein, we summarize the effects of fucosylation in digestive system inflammatory diseases and cancers, primarily concentrating on the intestine, stomach, liver, and pancreas, from the aspects of the genetic risks of fucosyltransferase mutation, the roles of aberrant fucosylated glycans as diagnostic biomarkers, and the molecular mechanisms of fucosylation-related gene-induced disorders. Finally, we discuss therapeutic strategies targeting fucosylation by fucose or fucosylation inhibitors. We aim to elaborate on the current understanding and provide novel insights into the role of fucosylation in digestive diseases, hoping to facilitate future studies and resolve clinical issues.

Clubfoot, medically termed congenital talipes equinovarus (CTEV), is a prevalent musculoskeletal birth defect, affecting approximately 0.3% of all live births. This serious congenital anomaly results from structural abnormalities in the foot and lower leg, leading to abnormal positioning of the ankle and foot joints. This review provides a comprehensive overview of the causative factors associated with CTEV and evaluates current therapeutic approaches. Although variations in genes encoding contractile proteins of skeletal myofibers have been proposed as contributors to the etiology of CTEV, no definitive candidate genes have been conclusively linked to increased risk. However, genes such as TBX4, PITX1, and members of the HOXA, HOXC, and HOXD clusters, as well as NAT2, have been implicated in the condition’s development, playing critical roles in limb development, muscle formation, and tissue differentiation. Also, Axin1 plays a key role in joint formation and skeletal development by inhibiting β-catenin-BMP signaling. It could significantly serve as a therapeutic target for fibular hemimelia and multiple synostoses syndrome. The exact mechanisms and the extent of their physical and genetic interactions remain subjects of ongoing research. Understanding the genetic determinants and cellular pathways involved in CTEV is crucial for unravelling the pathophysiology of this complex deformity.

Mitochondrial biogenesis (MB) is involved in the regulation of cellular energy metabolism, stress response, and survival. This review examines therapeutic approaches to acute kidney injury (AKI) that target MB, emphasizing clinical research findings and translational strategies in this field. AKI is a severe condition with high mortality and often leads to chronic kidney disease. AKI suppresses MB, resulting in mitochondrial dysfunction, oxidative stress, and further renal damage. Furthermore, studies have shown that ischemia-reperfusion-, sepsis-, and drug-induced AKI inhibit MB and subsequent kidney injury. Studies have shown that targeting MB through genetic and pharmacological interventions can alleviate AKI by restoring mitochondrial function and improving renal outcomes. Small molecule compounds, such as pyrroloquinoline quinone, ZLN005, and resveratrol, can enhance MB, offering potential therapeutic benefits. Nonetheless, further studies are needed to ensure efficacy across different models and mitigate related side effects. Future research should focus on optimizing drug design, understanding MB regulation, and conducting clinical trials to establish effective treatments for AKI.

Chimeric antigen receptor T (CAR T) cell therapy has achieved remarkable efficacy for patients with hematological malignancies. However, in vitro viral vector-mediated production of CAR T cells is time-consuming and expensive and impairs T cell function. On one hand, an elaborate manufacturing process not only impairs the function of CAR T cells but also limits its usage in patients with rapidly progressing diseases. On the other hand, high costs are incompatible with broad clinical applications for sizable populations. In vivo production of CAR T cells is a novel approach that can avoid complicated production processes and reduce costs through mass production. Additionally, in vivo production of CAR T cells does not damage the function of T cells compared with in vitro production. Early studies have demonstrated promising antitumor activity of in vivo CAR T cell therapy in preclinical models of hematological malignancies. In this review, we describe the latest developments of in vivo CAR T cell therapy and discuss its potential challenges for clinical application.

The abnormally active tumor vasculature provides a good blood supply for the rapid proliferation of tumors. The tumor microenvironment of tumor cells is associated with the secretion of a lot of angiogenic factors to promote the formation of blood vessels. However, the blood vessels are often irregular and immature. Additionally, the tumor tissue, in the process of its rapid proliferation, oppresses tumor blood vessels, causing hypoperfusion and leading to high interstitial pressure and hypoxia, which also results in changes to the fluid mechanics in the tumor microenvironment. Different fluid mechanics affect circulating tumor cell behavior and control various functions. A good mechanical microenvironment may be one of the important targets for inhibiting tumor proliferation and migration. Therefore, regulating tumor blood vessels to maintain a steady fluid mechanical microenvironment has the potential to be one of the key targets for tumor treatment. Numerous studies have demonstrated that certain natural medicines exhibit significant potential for inhibiting tumor growth and metastasis by selectively targeting tumor blood vessels, regulating the production of angiogenic cytokines, facilitating vascular normalization, etc. Furthermore, natural medicines enhance the anti-tumor effects of chemoradiotherapy and act as adjuvant agents to alleviate its associated side effects. This review summarizes the angiogenesis of the tumor microenvironment, changes induced by mechanical conditions, and the response of tumor cells and vasculature to different fluid shear stress to promote vascular normalization treatment strategies.

Oncolytic viruses (OVs), a kind of emerging therapeutics for treating tumors, are characterized by high replication efficiency, superior killing effects, and few adverse reactions, which have shown great application prospects in preclinical tumor treatment trials. To overcome the limitations of OV monotherapy, recent studies have found that combination therapy with other anti-tumor therapeutics, especially with immunotherapy, yields promising outcomes in tumor eradication. Due to the advancements in genetic engineering, the combination of OVs with novel immunotherapy, including cellular immunotherapy, adoptive cellular immunotherapy, immune checkpoint inhibitors, cancer vaccines, cytokines, and bi- or tri-specific T cell engagers, has greatly improved clinical outcomes and quality of life of tumor patients. In this review, we systematically summarize the latest progress of OVs combined with immunotherapy in tumor treatment and highlight the future directions of the combination strategies, which will promote the clinical application of OVs in tumor therapy.

Chitinase-3-like protein 1 (CHI3L1) is part of the glycoside hydrolase family 18. Despite lacking enzymatic activity, its unique structure allows it to bind to ligands, altering its steric configuration to mediate cell proliferation, inflammation, fibrosis, and carcinogenesis. In liver disease, CHI3L1 serves as a common diagnostic biomarker for hepatitis-related fibrosis. Additionally, CHI3L1 can predict the risk of non-alcoholic steatohepatitis, the progression of hepatic fibrosis, and the prognosis of alcoholic liver disease and hepatocellular carcinoma. It also aids in diagnosing and staging non-alcoholic fatty liver disease-related and alcoholic liver disease-related fibrosis, and in monitoring hepatitis-related fibrosis treatment. Furthermore, CHI3L1 is secreted by various cells, including hepatocytes, hepatic stellate cells, macrophages, and mesenchymal stem cells, to regulate hepatic injury, fibrosis, steatosis, and hepatocellular carcinoma through different signaling pathways. This review highlights CHI3L1's dual roles as both a biomarker and regulator in various liver diseases, aiming to broaden researchers' understanding of its potential applications.

Ferroptosis, a distinct regulated cell death process characterized by iron retention and lipid peroxidation, plays a crucial role in the survival of cancer stem cells (CSCs), key contributors to cancer initiation, progression, and recurrence. CSCs exhibit enhanced iron uptake and altered lipid metabolism, allowing them to evade conventional therapies and persist within the cancer microenvironment. Their resilience is linked to low reactive oxygen species levels, aiding survival under oxidative stress. Key regulatory pathways, including the cystine/glutathione axis, significantly modulate CSCs' sensitivity to ferroptosis by maintaining a balance between antioxidant defenses and pro-oxidative stressors. Targeting ferroptosis in CSCs offers promising therapeutic avenues for enhancing treatment efficacy and overcoming resistance. Strategies such as pharmacological inhibition of the SLC7A11 transporter, which reduces cysteine availability and glutathione levels, can potentiate ferroptosis in CSCs. Additionally, inducing dysregulation of iron metabolism or lipid peroxidation can selectively compromise CSCs' survival. Nanoparticle drug delivery systems that increase intracellular iron and reactive oxygen species levels are proving effective in targeting CSCs with minimal impact on normal cells. Ultimately, a comprehensive understanding of the interplay between ferroptosis and CSCs' biology is essential for developing innovative strategies aimed at eradicating these elusive cells, thereby improving cancer treatment outcomes and reducing recurrence rates.

Head and neck cancer, which includes cancers of the mouth, larynx, and pharynx, is one of the six most common cancers worldwide. Common risk factors include smoking, excessive alcohol consumption, betel nut chewing, and viruses such as HPV and EBV. Tumor cells often exhibit distinct metabolic characteristics compared with normal cells, highlighting a key area for potential intervention. By targeting these metabolic pathways, it is possible to influence tumor initiation and progression. Therefore, this review primarily describes the alterations in glucose metabolism, amino acid metabolism, lipid metabolism, and the immune system in head and neck cancer patients and discusses potential treatment strategies to advance the understanding of head and neck cancer and the development of therapeutic drugs for it.

Prostate cancer remains a major health problem, with its incidence ranking second among male malignancies worldwide. Recent studies have highlighted the critical role of the SOX family transcription factors, especially SOX2, in prostate cancer pathogenesis. SOX2 regulates the fate of cancer stem/progenitor cells, contributing to tumor initiation, development, and metastasis. Elevated SOX2 levels have been detected in prostate cancer tissues and are associated with higher tumor grade, aggressive phenotype, and poor prognosis. SOX2 also impacts various tumor biological behaviors, including cell proliferation, invasion, metastasis, resistance to apoptosis, and treatment resistance. This review highlights the role of SOX proteins in prostate cancer, focusing on the molecular mechanisms by which SOX2 drives cancer progression, elucidating the mechanisms controlling its activity, and emphasizing its potential as a therapeutic target.

The Human Genome Project marked a milestone in scientific exploration, unraveling the genetic blueprint of humanity. However, expectations of direct gene–disease associations gave way to realizing the complexity of genetic interactions, especially in polygenic diseases. This review explores the legacy of the HGP and subsequent advancements in genomic technologies, particularly next-generation sequencing, which have enabled more profound insights into the non-coding genome's role in gene regulation. While initially dismissed as “junk” DNA, non-coding regions are now officially approved as critical gene expression and genome organization regulators. Through integrative genomics approaches and advanced computational methods, researchers have unveiled the intricate network of enhancers, promoters, and chromatin modifications orchestrating gene expression. High-throughput sequencing techniques and functional assays have identified non-coding variants associated with numerous diseases, challenging the conventional focus on coding sequences in genomic studies. By elucidating the regulatory mechanisms governing gene expression, researchers can advance precision medicine approaches and develop novel diagnostic tools. As genomic research continues to evolve, a vast landscape is waiting to be explored, promising transformative insights into human health and disease. This review provides a comprehensive overview of the non-coding genome's role in gene regulation and its implications for understanding complex diseases and developing targeted therapeutic interventions.

Glioma, an aggressively malignant brain tumor with a poor prognosis, comprises nearly 50% of all primary malignant brain tumors. Despite its significance in other cancers, the role of coiled-coil domain containing 86(CCDC86) in glioma remains largely unexplored. Our study revealed a significant up-regulation of CCDC86 expression in glioma tissues, correlating notably with patient age, tumor recurrence, and pathological grade. Moreover, elevated CCDC86 level was associated with a worsened prognosis among glioma patients. Functional assays demonstrated that CCDC86 knockdown attenuated glioma cell proliferation and migration while inducing apoptosis and cell cycle arrest in vitro and inhibited tumorigenesis in vivo. Furthermore, ATF3 emerged as a downstream target gene of CCDC86, as its knockdown could counteract the oncogenic effects induced by CCDC86 overexpression in glioma cells. Mechanistically, CCDC86 promoted the transcriptional regulation of ATF3 by BHLHE40 through interaction with it, stabilizing the expression of ATF3. Additionally, our investigation unveiled a potential mechanism whereby CCDC86 activated the ERK signaling pathway through ATF3, thus influencing glycolysis to drive tumor progression. In conclusion, our study highlights the pivotal role of CCDC86 in glioma progression, suggesting its potential as a therapeutic target for the development of novel glioma treatments.

DNA methylation is a key epigenetic alteration in tumorigenesis, but its diagnostic value in early-stage lung cancer remains unclear. In this study, tissue and plasma samples from patients with lung cancer or benignity were analyzed. Methylation profiles were obtained using bisulfite sequencing and compared with selected lung cancer-specific markers. Diagnostic prediction models were constructed using these markers, with their efficacy assessed by sensitivity, specificity and area under the curve (AUC). In the tissue cohort, 276 markers were found to be significantly differentially methylated in lung cancer (FDR < 0.05). A diagnostic prediction model using six markers showed promising performance in both the training cohort (sensitivity = 90%; specificity = 97%; AUC = 0.988) and the validation cohort (sensitivity = 92%; specificity = 94%; AUC = 0.977). In the plasma cohort, a diagnostic prediction model using nine markers achieved a sensitivity of 98% and specificity of 100% (AUC = 0.998) in the training cohort, a sensitivity of 81% and specificity of 59% (AUC = 0.791) in the validation cohort. Furthermore, we observed a significant correlation between delta methylation changes in tissue and plasma in the paired patient cohort. Additional analysis based on methylation haplotypes identified 1222 differentially methylated regions in tissue samples, mainly enriched in DNA replication-related pathways. Additionally, correlations between DNA methylation and clinical characteristics revealed significant differential methylation patterns between smokers and non-smokers . Thus, DNA methylation in both tissue and plasma holds potential as a biomarker for the early diagnosis of lung cancer.

Increased mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) imposes an urgent need to elucidate the pathogenesis of MASLD so that novel therapeutic strategies may be identified. Here, we delineate the mechanism of microRNA-34a-5p (miR-34a) in the progressive liver injury of MASLD and liver fibrosis. Specifically, liver tissue from patients with obesity-associated hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis, as well as liver tissues from a human MASLD-like mouse model, were utilized for this study. We found that lipotoxicity resulting from obesity or saturated free fatty acid treatment induced miR-34a expression in human liver tissue or mouse hepatocytes, which was accompanied by dysregulation of lipoprotein metabolism, activation of inflammation, and ballooning degeneration of hepatocytes. Moreover, increased cellular miR-34a induced by treatment with saturated fat, palmitic acid, or transfection of miR-34a mimic was released from injured hepatocytes into the conditional cell culture media, which mediated pathological communications between hepatocytes and hepatic stellate cells, activated pro-fibrogenic signaling in hepatic stellate cells, and induced extracellular matrix remodeling. These phenotypes were recapitulated in a human MASLD-like mouse model in which MASLD and liver fibrosis were induced via streptozotocin treatment and high-fat feeding. Elevated expression of miR-34a was found in mouse liver tissues, which conveyed the progressive liver injury from steatosis to MASH and liver fibrosis. Our findings demonstrate that elevated miR-34a induced by lipotoxicity and metabolic inflammation are key driving factors in the progressive liver injury from simple steatosis to MASH and liver fibrosis.

CISD1, an outer mitochondrial membrane iron-sulfur cluster protein, regulates intracellular iron levels, oxidative stress, and mitochondrial dynamics, playing critical roles in cellular bioenergetics and redox homeostasis. Although CISD1 has been identified as a prognostic biomarker in specific cancers, its broader implications in tumorigenesis, cancer progression, and immunotherapy remain unclear. Given the heterogeneity of cancer and the need for robust biomarkers across cancers, this study conducts the first comprehensive pan-cancer analysis of CISD1 by evaluating its roles in cancer and treatment. We obtained and analyzed data from databases including TCGA, GTEx, THPA, GEPIA2.0, SangerBox, cBioPortal, TIMER2.0, CAMOIP, DAVID, SRPLOT, and TISIDB. Our findings reveal significant alterations in CISD1 expression at both transcriptional and translational levels, as well as gene mutations across multiple cancers, indicating its potential as a diagnostic biomarker and its involvement in cancer development and progression. CISD1 dysregulation is linked to poor clinical outcomes, as shown through its impact on patient prognosis. GO and KEGG analyses show that CISD1 plays critical roles in cellular bioenergetics. Notably, CISD1 expression is significantly correlated with tumor stemness indices, tumor mutation burden, microsatellite instability, and immune checkpoint proteins in multiple cancers, and altered CISD1 levels are also observed in patients responding to immunotherapy, further supporting its role not only in prognosis but also as a key predictor in immunotherapy responses and outcomes. Our findings demonstrate CISD1 as a reliable and promising diagnostic, prognostic, and immunotherapeutic biomarker for multiple cancers, emphasizing its crucial role in cancer biology and potential to guide personalized cancer therapies.

Understanding metastatic osteosarcoma relies on defining the complexity of cell types, their associated molecular profiles, and interactions among cells in the tumor microenvironment. Here, we integrated single-cell and bulk gene expression datasets and revealed that metastatic lesions were highly enriched for GTSE1+ osteoblasts (OB). Under the regulation of E2F family members, GTSE1+ OB cells harbored enhanced proliferation activity and high differentiation potential. Augmentation of GTSE1 enhanced the abilities of cell migration and invasion, while silencing of GTSE1 impaired the abilities in human OB cell lines. Furthermore, cellular communication analysis showed the cross-talk between GTSE1+ OB cells and CD8+ T cells in metastasis was achieved through the MIF-(CD74-CXCR4) pair. Spatial transcriptomic data revealed that MIF-CD74 and CXCR4-MIF/CD74 showed a higher positive correlation in undifferentiated pleomorphic sarcoma than leiomyosarcoma. Correlation analysis unveiled that GTSE1+ OB cells and monocytes were the negatively correlated populations at the single-cell level, a finding validated in 4 independent osteosarcoma datasets comprising 226 samples. Our findings suggest that GTSE1 overexpression serves as a potential biomarker for metastasis in osteosarcoma and provides a promising strategy to prevent metastasis by targeting GTSE1+ OB cells.

Age-related macular degeneration (AMD) poses a significant threat to the vision of the elderly population globally. Unfortunately, there is no effective treatment available for dry AMD. In this study, we utilized human retinal organoids (ROs) stimulated with sodium iodate to establish a model for dry AMD. We assessed the apoptosis of retinal organoid cells and conducted RNA sequencing to analyze molecular changes. Our findings indicate that metformin and the fetal hemoglobin (HbF) inducer TN1 could protect ROs from sodium iodate induced damage and restore retinal function in murine model. The administration of metformin and TN1 alleviated apoptosis in ROs and improved visual function. Studies of molecular mechanisms indicated that the protective effects of metformin and TN1 may be related to the HMOX1 gene, providing valuable insights for the development of new therapies for dry AMD via targeting HMOX1 and its downstream pathways.

Lens epithelium, a fundamental biological structure pivotal for maintaining normal vision, can be disrupted, leading to the development of cataracts. The epithelial-mesenchymal transition has been proven to be the key factor of secondary cataract progression. However, the underlying mechanism of epithelial-mesenchymal transition in lens epithelial cells remains unclear. In this study, we conducted a comprehensive analysis and classification annotation of single-cell transcriptomic sequencing (scRNA-seq) data. This data was derived from fetal eye tissues of ages ranging from 9 to 23 weeks, sourced from our previously published research. Trajectory analysis showed a differentiation trend from epithelial cell to fiber cell. Furthermore, an integrative analysis of accessible-chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) data revealed that the transcription factor ATF6 may play a pivotal role in maintaining the homeostasis of lens epithelial cells. Subsequent in vitro experiments revealed that inhibition of ATF6 could alleviate epithelial-mesenchymal fibrosis by reducing STAT3 phosphorylation. Collectively, our study presents an atlas of lens epithelial cell development at the single-cell resolution, uncovering evidence that heightened ATF6 activity could potentially promote epithelial-mesenchymal transition in lens epithelial cells.

Oral squamous cell carcinoma in the background of/with oral submucous fibrosis (OSCC-OSF) has a unique etiology and is clinically distinct from other OSCCs. We previously identified ADAMTS9-AS2 as a functional tumor suppressor in OSCC-OSF through the regulation of PI3K-AKT signaling. However, its role in metabolic modulation and the underlying mechanisms remain unclear. In this study, we reported for the first time that ADAMTS9-AS2 suppressed aerobic glycolysis by cooperating with let-7a-5p in OSCC cells. Mechanistically, let-7a-5p inhibited HK2 expression by targeting its 3′-UTR, further deregulating glycolytic function, while enhancing HK2 expression rescued the inhibitory effects of the ADAMTS9-AS2/let-7a-5p axis on aerobic glycolysis and OSCC cell growth. Exosomal ADAMTS9-AS2 regulated metabolic reprogramming during OSCC tumorigenesis. ABC transporters in lipid and pyrimidine metabolism were significantly enriched pathways. Changes in several key metabolites were identified after ADAMTS9-AS2 exosome treatment, including increased levels of DL-glutamic acid and D-mannose, along with decreased levels of cytidine and D-maltose. Thus, our findings demonstrate that ADAMTS9-AS2 drives let-7a-5p binding to HK2 to suppress cell growth in OSCC by abolishing aerobic glycolysis. Our data on metabolic reprogramming have greatly expanded the role of the ADAMTS9-AS2/let-7a-5p axis as a key regulator of metabolism during OSCC tumorigenesis.

Bladder cancer (BLCA) is a common malignant tumor of the urinary system, with significant morbidity and mortality rates worldwide. The MEN1 gene, encoding the menin protein, plays a regulatory role in several cancers. However, the role played by menin in BLCA remains elusive. In this study, our data demonstrated that the expression of menin was significantly up-regulated in BLCA tissues versus normal tissues, and the high expression of menin was strongly correlated with poor prognosis of BLCA patients. In vitro, silencing MEN1 inhibited cell proliferation and induced cell cycle arrest at the G1/S phase in BLCA cells. Furthermore, RNA sequencing analysis revealed that MEN1 knockdown significantly inhibited the Wnt/β-catenin signaling in BLCA cells. Meanwhile, we further confirmed that β-catenin served as a critical downstream effector of menin in BLCA cells. Mechanically, chromatin immunoprecipitation analysis demonstrated that menin promoted CTNNB1 (catenin beta 1) transcription through binding to the CTNNB1 proximal promoter in BLCA cells. Interestingly, menin collaborated with TFAP2C, a regulator of β-catenin in BLCA cells, to enhance the transcription of the CTNNB1 gene. More intriguingly, BAY-155, a menin molecule inhibitor, inhibited cell growth of BLCA cells both in vitro and in vivo by suppressing the expression of menin, TFAP2C, and β-catenin. Our current work unveils an important role of the menin in triggering the TFAP2C/β-catenin axis, which contributes to cell proliferation of BLCA cells. Therefore, menin might be served as a new therapeutic target for BLCA.

Microglial activation triggers the inflammatory cascade and exacerbates brain injury following ischemic stroke. Middle cerebral artery occlusion (MCAO) modeling increased the expression of nuclear factor of activated T cells 5 (NFAT5) in microglia. However, the role of microglial NFAT5 in ischemic stroke remains unclear. Here, our findings indicated that microglial NFAT5 knockdown reduced the expression of pro-inflammatory factors, microglial activation, and neutrophil infiltration, ultimately ameliorating cerebral infarction and neurological deficits in mice following MCAO. Additionally, we treated hippocampal neuronal cells (HT22) with a conditioned culture medium from a microglia cell line (BV2) to simulate microglia-induced neuronal injury in vitro. We observed that NFAT5 knockdown attenuated the expression of pro-inflammatory factors in BV2 cells and reduced apoptosis in HT22 cells. Previously, our published work reported that the NOD-like receptor pyrin domain-containing 6 (NLRP6) inflammasome contributed to inflammatory injury after MCAO. In this study, we discovered that NFAT5 promoted the transcriptional activity of the Nlrp6 promoter through its −1527 bp to −1518 bp element. Notably, our results also demonstrated that NFAT5 regulated the stability of NLRP6 mRNA via the 5′UTR of Nlrp6. Thus, our findings reveal the pivotal role and partial mechanism of microglial NFAT5 in neuroinflammation following ischemic stroke.

RAB26 is important in the regulation of membrane trafficking and cell motility. Recently, RAB26 has received increasing attention in cancer research. However, the functional role of RAB26 in prostate cancer (PCa) remains to be elucidated. Single-cell RNA sequencing data (GSE141445) analysis indicated that RAB26 was widely expressed in PCa cells, especially in luminal cells and basal cells. High RAB26 expression in patients was found to be significantly associated with advanced pathological stage, Gleason score, and poor prognosis. Furthermore, our experimental results showed that RAB26 promoted the proliferation, migration, and invasion of PCa cells, as well as influenced the stemness of PCa cells in vitro. Besides, the transcription sequence indicated that RAB26 might promote the metastatic potential of PCa by promoting epithelial–mesenchymal transition through cascades of MAPK/ERK pathways. Finally, we found that RAB26 activated TWIST1 expression and consequently induced epithelial–mesenchymal transition, based on its interaction with the TWIST1 promoter. In conclusion, RAB26 promotes the aggressive progression of PCa and stemness of tumor cells, which is an independent biomarker for the prognosis of PCa.

Glioblastoma multiforme (GBM) is the deadliest form of brain tumor, and effective treatments are lacking. Thus, a new generation of effective treatments is urgently needed. B-cell lymphoma 6 (BCL6) is a transcription factor that functions to suppress the transcription of DNA damage response genes, halting cell death in response to DNA damage. Here, we identified BCL6 as a lynchpin in GBM, the expression of which was greater in GBM cells than in normal cells and associated with poor survival in GBM patients. The silencing of BCL6 additionally affected GBM cell proliferation and triggered cellular damage. Furthermore, we reported the identification of YK01, a novel small-molecule inhibitor of BCL6. YK01 exhibited excellent anti-GBM bioactivity and caused apoptosis; importantly, YK01 significantly inhibited the growth of GBM cells both in vitro and in vivo. Moreover, the combination of YK01 and temozolomide treatment significantly suppressed the growth and metastasis of tumors in vivo and prolonged the survival of mice with tumors. In summary, our findings reveal that BCL6 appears to play a crucial role in GBM and may be a therapeutic target for treating this incurable condition.

Lenvatinib is widely used as a first-line chemotherapy for advanced hepatocellular carcinoma (HCC), a highly metastatic and recurrent cancer. However, HCC cells often develop resistance to lenvatinib, thus reducing its efficacy. This study aims to investigate the impact of STARD4, a crucial cholesterol transporter, on HCC growth and lenvatinib resistance, as well as explore the involvement of the EGFR/PI3K/AKT signaling pathway in STARD4's role. Analysis of clinical samples from HCC patients revealed increased expression of both STARD4 and EGFR in tumor tissues, with a strong correlation between STARD4 expression and malignancy progression. In vitro and in vivo studies demonstrated that STARD4 promoted HCC growth and hindered lenvatinib's anti-tumor effect, while STARD4 down-regulation exerted opposite effects. Further investigation revealed that depletion of STARD4 increased cholesterol accumulation in the plasma membrane, resulting in reduced EGFR phosphorylation. Moreover, cholesterol depletion attenuated these effects, suggesting STARD4 activates EGFR/PI3K/AKT signaling in a cholesterol-dependent manner. To elucidate the underlying mechanism of lenvatinib resistance, we established the lenvatinib-resistant HCC cell lines and found increased stimulation of both STARD4 and EGFR signaling. Furthermore, the EGFR inhibitor erlotinib suppressed the promotion of HCC progression by STARD4, reinforcing its role in activating the EGFR/PI3K/AKT pathway. In conclusion, this study demonstrates that STARD4 enhances HCC growth and lenvatinib resistance by regulating cholesterol homeostasis and activating the EGFR/PI3K/AKT pathway. These findings suggest STARD4 as a potential molecular biomarker for predicting lenvatinib resistance and as a therapeutic target in HCC treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by excessive hepatic lipid accumulation. This study evaluated the therapeutic effects and molecular mechanisms of tirzepatide, a dual GIP and GLP-1 receptor agonist, in treating hepatic steatosis. Eight-week-old C57BL/6J mice were fed either a high-fat diet or a high-fat, high-fructose, and high-cholesterol diet for 12 weeks to induce MASLD. From week 8, some mice received weekly intraperitoneal tirzepatide injections for four weeks. Tirzepatide significantly reduced body and liver weight gain. Histological analysis confirmed decreased hepatic vacuolation and lipid deposition. The drug also lowered serum glucose levels and reduced liver triglyceride and cholesterol content without causing liver injury. Transcriptome analysis showed that tirzepatide downregulated mitochondrial oxidative phosphorylation pathways. It also decreased hepatic expression of CD36 and odorant-binding protein 2A, both involved in lipid uptake. Importantly, tirzepatide did not significantly alter other major liver metabolic pathways. In adipose tissue, it reduced CD36 and odorant-binding protein 2A expression and upregulated adipose triglyceride lipase, suggesting enhanced lipolysis. However, it had no effect on CD36 levels in skeletal muscle. These results suggest that tirzepatide may be an effective treatment for MASLD by reducing liver fat accumulation and modulating lipid metabolism in extrahepatic tissues.

Successful placental development and pregnancy rely on effective extravillous trophoblast (EVT) invasion. The mechanisms underlying inadequate EVT invasion in recurrent spontaneous abortion (RSA) remain unclear. WAS/WASL interacting protein family member 1 (WIPF1), the key regulator of cytoskeletal dynamics, is exclusively expressed in first-trimester placental EVTs. Knockdown experiments revealed WIPF1's crucial involvement in successful placental development; reduced levels impaired cell migration, while overexpression induced the opposite effects. Moreover, WIPF1 knockdown in hTSC-derived EVTs hampered trophoblast differentiation. WIPF1 interacted with ACTN4 to regulate podosome formation, matrix degradation, and actin polymerization, potentially mediated by its ARG54 site. Notably, WIPF1 was significantly down-regulated in human RSA patient EVTs and RSA mice trophoblast giant cells (CBA/J × DBA/2). This association suggests WIPF1 as a potential key player in RSA pathogenesis. In conclusion, our study spotlights WIPF1 as a pivotal factor in EVT invasion, emphasizing its multifaceted roles and implications in pregnancy complications like RSA.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of oral antidiabetic drugs, but they appear to have additional metabolic effects on circulating metabolites. At present, relevant studies have also proved that SGLT2 inhibition is related to the generation of diseases through metabolites.1,2 However, the impact of SGLT2 inhibition on cancer still needs to be explored. This study aimed to analyze the relationship between SGLT2 inhibition, blood metabolites, and lymphocytic leukemia by Mendelian randomization analysis.