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 landscape of cancer diagnostics has been fundamentally transformed by the emergence of minimal residual disease (MRD) detection technologies, with epigenetic mechanisms playing a pivotal role in understanding the molecular complexity of cancer.1 Epigenetic modifications, particularly DNA methylation (DNAm) and chromatin accessibility (ChrAcc), have emerged as critical determinants in tracking and comprehending residual cancer cells that persist after primary treatment.2 DNAm represents a sophisticated molecular mechanism through which cancer cells maintain their adaptive state, enabling MRD detection with unprecedented precision.3 Recent single-cell sequencing technologies have revealed that methylation patterns serve as dynamic molecular signatures that can distinguish between active and dormant cancer cell populations.4 These epigenetic modifications act as molecular switches, regulating gene expression and cellular plasticity without altering the underlying genetic code, thus providing a nuanced understanding of cancer cell behavior beyond traditional genetic analysis.5 ChrAcc, another crucial epigenetic dimension, offers complementary insights into MRD detection. By examining the openness of chromatin regions, specific genomic loci that remain accessible in residual cancer cells can be identified, even after extensive treatment.2 This approach allows the identification of rare cancer cell populations that might otherwise escape conventional detection methods (Fig. 1A).

Meiosis, a specialized cell division process that generates haploid gametes for sexual reproduction, includes the crucial phase of prophase I, where homologous chromosomes pair, synapse, and undergo recombination. Prophase I is divided into five stages—leptonema, zygonema, pachynema, diplonema, and diakinesis—with pachynema, lasting approximately six days in mice, being the longest and playing a uniquely critical role in meiosis. The regulatory mechanisms driving pachynema progression are intricate and not yet fully understood, though the pachytene checkpoint is most frequently implicated as crucial for ensuring proper meiotic progression. Additionally, three key meiotic checkpoints play critical roles in maintaining the fidelity of pachynema progression: the DNA damage checkpoint, which acts as a recombination-dependent arrest mechanism, triggering apoptosis if double-strand breaks (DSBs) are not fully repaired during pachynema; the synapsis checkpoint, which ensures accurate chromosome pairing and synapsis, eliminating meiocytes with asynapsis or synaptic errors; and meiotic sex chromosome inactivation (MSCI), which mediates the transcriptional repression of unsynapsed regions in the sex chromosomes within the XY body, with defective MSCI leading to complete meiotic arrest and elimination of spermatocytes at the mid-pachytene stage.1 However, several studies have suggested that non-checkpoint mechanisms may also play important roles in pachynema progression. For instance, while the underlying molecular mechanisms remain unclear, the absence of proteins such as HSPA2 and EIF4G3 leads to meiotic arrest at the pachytene stage, despite no significant cytological defects in DSB repair, synapsis, or MSCI.2 These findings raise the possibility that, in addition to the pachytene checkpoint, which monitors and ensures proper recombination, synapsis, and MSCI, other distinct regulation mechanisms for pachynema progression may also exist.

The phosphoinositide 3-kinase (PI3K) family and the PI3K/AKT signaling pathway have been recognized as key players in oncogenic processes such as cell survival, metabolism, and metastasis. PI3K transduces signals from growth factors into intracellular responses by converting PI (4,5) P2 into PI (3,4,5) P3, activating the serine–threonine protein kinase AKT and downstream pathways. The PI3K/AKT pathway is tightly regulated, but in cancer, it can be constitutively activated through mutations in PI3K enzymes or receptor tyrosine kinases, such as EGFR or HER2. An alternative mechanism for activating the PI3K/AKT pathway involves the direct interaction between PI3K and the RAS protein. This interaction facilitates the recruitment of PI3K to the plasma membrane, promoting its catalytic activity.1 Disruption of the RAS-PI3Kα interaction alters tumour formation, highlighting its role in tumourigenesis.2 Based on the role of the PI3K/AKT pathway in cell growth and proliferation, it has been recognized as an attractive target for treating cancer. Several PI3K inhibitors have been characterized, some of which have already been approved for therapeutic use.1 However, most of these inhibitors are primarily ATP-competitive, which limits their specificity. While effective in suppressing tumor growth, their systemic application often causes hyperglycemia and insulin feedback by disrupting normal PI3K activity, limiting their tolerability and long-term clinical use3 (Fig. 1A). In a recent study, Simanshu DK et al4 presented an alternative approach by targeting the protein–protein interaction between RAS and the Ras-binding domain (RBD) of PI3Kα, thereby decoupling oncogenic activation from essential metabolic signaling.

Urologic diseases, including benign and malignant conditions, impose a major global health burden.1 However, therapeutic development remains limited by an incomplete understanding of causal molecular drivers.2 Here, we performed a genome-wide Mendelian randomization analysis integrating blood-derived expression quantitative trait loci (eQTL) with genome-wide association study (GWAS) data, focusing on druggable genes with cis-eQTL evidence to systematically prioritize and validate therapeutic targets for urologic diseases (Fig. S1). Through two-sample Mendelian randomization, we identified genes with putative causal roles in urologic diseases, including leukocyte receptor tyrosine kinase (LTK) for bladder cancer and cyclin A2 (CCNA2) for benign prostatic hyperplasia (BPH). Functional annotation revealed key pathways and protein–protein interaction networks relevant to disease pathogenesis. Both genes demonstrated potential clinical relevance in external datasets. These findings provide genetically supported targets with translational potential and may contribute to the development of more effective treatment strategies for urologic diseases.

Here we report a 10-year-old girl diagnosed with dilated cardiomyopathy, decompensated heart failure, and evidence of global end-organ hypoperfusion in the setting of severely depressed biventricular systolic function. Exome sequencing revealed a novel germline heterozygous frameshift variant resulting from a 2-bp deletion, c.1496_1497del (p.Pro499Leufs∗104) in the PR-domain containing 16 (PRDM16) gene, functionally proven to result in PRDM16 deficiency, evidenced by pretermination of PRDM16 protein. Furthermore, the consistent presence of the PRDM16 variant in affected family members, and its absence in non-affected family members, combined with a strong maternal family history of cardiomyopathy, provides compelling support for the pathogenicity of the PRDM16 variant. Nevertheless, there is no obvious sex bias in our reported family in terms of PRDM16-related cardiomyopathy. We showed that this variant led to impaired mitochondrial function and ATP production. Based upon the collective results of functional studies, clinical features, and family history, this novel heterozygous frameshift germline variant in PRDM16 was determined to be the cause of the familial cardiomyopathy and heart failure. This novel pathogenic PRDM16 variant has potential utility in diagnosis and prognosis and underscores the critical and unique role of PRDM16 in human cardiomyopathy.

Cystathionine-β-synthase (CBS) is a key metabolic enzyme traditionally associated with homocysteine metabolism. Recent studies have uncovered its broader role in tumor biology,1 yet its impact on the tumor immune microenvironment remains largely unexplored. Tumor immunotherapy has rapidly advanced, with strategies such as immune checkpoint inhibitors, chimeric antigen receptor-T cell therapy, and tumor vaccines revolutionizing cancer treatment. Extensive analyses have summarized these approaches and their underlying mechanisms.2 However, metabolic regulators like CBS may also contribute to tumor immune escape, offering novel therapeutic targets. Here, we report for the first time that CBS promotes tumor immune evasion by destabilizing major histocompatibility complex class I (MHC-I) molecules, revealing a previously unrecognized link between tumor metabolism and immune surveillance.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized predominantly by renal abnormalities, which constitute the leading cause of early mortality in patients with BBS. Genotype–phenotype analyses indicate that mutations in genes encoding components of the BBSome core complex (BBS2-BBS7-BBS9) correlate with higher penetrance of renal manifestations1; however, the underlying pathogenic mechanisms remain unclear. Within the core complex, the BBS7 protein occupies a unique and pivotal role, directly interacting with chaperone complexes and initiating BBSome assembly.2 Studies utilizing mouse models carrying BBS7 mutations have failed to fully recapitulate the human BBS phenotype, suggesting either species-specific differences or distinct pathogenic thresholds in ciliopathies.3 Thus, establishing genetically consistent, humanized disease models is essential. Human induced pluripotent stem cells (hiPSCs) derived from patients carry disease-specific genetic and epigenetic information, rendering them ideal tools for modeling various disorders, including BBS. In this study, we identify a novel BBS7 mutation, c.754G > A(p.D252N), and established a kidney lineage model from patient-specific hiPSCs harboring compound heterozygous mutations in the BBS7 gene, aimed at investigating the effects of BBS7 mutations on renal development and elucidating the underlying pathogenic mechanisms.

Liver hepatocellular carcinoma (LIHC) represents the predominant subtype of liver cancer, which is characterized by high rates of occurrence and fatality, and imposes a significant burden on health systems worldwide.1 Mitochondria have garnered significant attention within the context of cancer research as key organelles. Mitochondrial dynamics constitute a part of the mitochondrial quality control system, encompassing mitochondrial fission, fusion, mitophagy, and transport, which are critical for maintaining mitochondrial function and cellular homeostasis.2,3 In cancer, mitochondrial dynamics play a significant role in tumor development, progression, and response to therapy. The balance between fission and fusion is tightly regulated, and dysregulation of these processes is often observed in cancer cells, contributing to their altered metabolism, resistance to apoptosis, and increased invasiveness.4 There has been a growing emphasis on mitochondrial dynamics-related genes (MDRGs) in oncology.5 However, comprehensive studies exploring the roles of MDRGs in LIHC are relatively rare.

Secreted components from the tumor microenvironment actively drive the development and progression of cancer cachexia. These cancer cachexia tumor factors (CCTFs) trigger systemic inflammation, metabolic alterations, skeletal muscle wasting, and adipose tissue lipolysis. Many of these factors are members of the cytokine–cytokine receptor interaction (CCRI) pathway, which is particularly enriched in tumor types highly associated with cachexia. For example, pancreatic ductal adenocarcinoma (PDAC) has the highest prevalence of cachexia and exhibits the highest number of overexpressed secreted genes. Our previous pan-cancer study demonstrated that secretory genes (tumor secretome) belonging to the CCRI pathway are up-regulated in tumors highly associated with cachexia.1 PDAC expressed the highest number of secreted genes from the CCRI pathway. Considering the potential of this pathway to have other CCTFs not previously associated with cachexia, it is crucial to determine a core of genes representative of the pathway in the context of cancer cachexia. Moreover, we expect to distinguish the primary source of CCTF by analyzing tumor transcriptomes (bulk and single-cell). Therefore, we aimed to investigate the secretome genes related to the CCRI pathway in 12 cancer types with different prevalences of cachexia, thereby generating what we called the core of cancer cachexia tumor factors (core-CCTF).

According to the World Health Organization (WHO), approximately 890 million people in the world were living with obesity in 2022. In South Korea, the prevalence of obesity has gradually increased, rising from 30.2% to 38.4% (2012–2021).1 Ubiquitin-specific protease 17 (USP17) significantly impacts critical cellular processes, including cell proliferation and oncogenesis.2 However, the role of USP17 in adipogenesis, a key process in obesity development, remains incompletely understood. Here, we investigated the functions of USP17 and the underlying mechanisms in 3T3-L1 adipocyte differentiation. Notably, a remarkable reduction in USP17 expression was observed following the induction of differentiation, largely due to dexamethasone. We then identified USP17 as a negative regulator of adipogenesis, as indicated by reduced lipid accumulation and down-regulation of adipogenic genes. Furthermore, USP17's deubiquitinating activity was indispensable for its regulation of adipocyte differentiation. Moreover, we identified histone deacetylase 1 (HDAC1) as a direct substrate of USP17. By stabilizing HDAC1 through deubiquitination, wild-type USP17, but not the catalytically inactive mutant USP17 (C89S), suppresses the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ). However, HDAC1 was found to partially counteract the resulting increase in PPARγ activity induced by USP17 (C89S). Overall, our findings highlight the potential of USP17 as a promising therapeutic target for obesity therapy.

Stimulator of interferon gene (STING), a key innate immune adapter, senses cytosolic DNA to trigger type I interferon responses and is linked to cancer and autoimmune disorders.1,2 Beyond canonical signaling, STING acts as a proton channel promoting non-canonical autophagy and inflammation,3 while its nuclear translocation may facilitate DNA repair.4 Dixon et al identified STING redistributing from inner to outer nuclear membranes upon dsDNA or dsRNA stimulation.5 Nevertheless, the potential role of nuclear STING remains largely unexplored. In our study, we found that poly(ADP-ribose) polymerase (PARP) inhibitor-induced DNA damage triggered STING nuclear translocation in cancer cells. Chromatin immunoprecipitation sequencing (ChIP-seq) identified nuclear STING targets linked to chromatin remodeling and enriched transcriptional motifs. RNA sequencing (RNA-seq) data from STING wild-type and knockout cell lines confirmed nuclear STING's necessity for innate immune activation and chromatin remodeling. Our findings demonstrate that STING undergoes nuclear translocation, where it alters the immune response and chromatin remodeling of cancer cells. These results reveal novel molecular targets and non-canonical functions of nuclear STING, providing a framework for developing targeted cancer therapies to modulate STING activity.

Breast cancer (BRCA) is one of the most prevalent cancers globally, with high occurrence and death rates.1 Although the TOR1B is known to be essential for regulating cell balance and reacting to endoplasmic reticulum stress, its impact on breast cancer is not yet fully understood.2,3 This study is the first to provide a thorough analysis of TOR1B in BRCA. TOR1B expression was significantly elevated in tumor tissue across the GSE15852, GSE109169 and TCGA-BRCA cohorts. Patients were then divided into high and low groups according to the expression level of TOR1B. The low expression group of TOR1B was characterized by a favorable survival outcome and may benefit from immunotherapy, while the high expression group of TOR1B was associated with elevated infiltration levels of immune cells and immune checkpoints. Moreover, three drugs (ZSTK474, navitoclax, and ABT-737) from CTRP and five drugs (meclizine, NVP-BVU972, propranolol, BMS-986020, and SR-27897) from the PRISM database were screened for the high TOR1B expression group. Single-cell analysis results demonstrated that TOR1B was highly expressed in monocyte. Finally, the overexpression of TOR1B promoted the proliferation, migration, and invasion of BRCA cells. These results indicate that TOR1B is a promising prognostic marker for predicting the survival of BRCA patients.

Over the past decade, transcriptomics has emerged as a vital tool to study inter- and intra-sample heterogeneity. In acute myeloid leukemia, comparison of RNA sequencing with whole genome or exome sequencing has revealed that RNA sequencing enables identification of expressed gene fusions, single-nucleotide and short insertion/deletion variants, and whole-transcriptome expression information, thus offering the greatest diagnostic return.1 Furthermore, by elucidating distinct molecular subtypes, transcriptomics also enables the development of personalized therapeutic strategies.2,3

PLIN4-related myopathy is a rare autosomal dominant disorder first described in 2020 in a large Italian family,1 presenting with weakness of lower distal limbs often combined with upper distal limbs, and with scapular and pelvic muscle as the predominant pattern of muscle involvement, without any relevant cardiac or respiratory implications.2 This myopathy was linked to a pathogenic expansion in the PLIN4 gene,1 encoding for perilipin 4 protein, whose function in the muscle is still unknown. This possesses an amphipathic region composed of 31 highly similar but not identical repeats, each of them formed by 99 nucleotides, corresponding to 33 amino acids.3 The reported mutation affects the highly repetitive exon 5 of the gene, and is due to the expansion of a single repeat increasing the number of 33-amino acid repeats from 31 to 40 (9 extra repeats).1 This expansion results in the accumulation of perilipin 4 in the subsarcolemmal region of the myofibers and within the vacuoles, with activation of the specialized aggrephagy pathway for the degradation of protein aggregates through autophagy. Over time, the elimination of accumulated vacuoles likely becomes a challenge, as vacuoles continue to form and fuse with each other, compromising the spatial organization of the fibers. This prevents the fibers from contracting properly, thus leading to their degeneration.

Extrachromosomal circular DNAs (eccDNAs) have been implicated in the pathogenesis of various diseases, particularly in cancer, where they contribute to gene amplification and oncogene expression. However, the regulatory mechanisms of eccDNAs in type 2 diabetes mellitus (T2DM) during both the early and late stages remain unknown. Here, we employed circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) to identify and analyze eccDNAs in pancreatic islets of T2DM mice at 8- and 24-week time points. As a result, the differentially expressed eccDNAs were 76 and 5422 in the 8- and 24-week groups, respectively. KEGG analysis showed that the glucagon signaling pathway was significantly enriched in the 8-week group. However, in the 24-week group, the pathways were primarily enriched in the phosphatidylinositol signaling system, the Wnt signaling pathway, pathways related to cancer, and the Rap1 signaling pathway. In particular, Wnt7acircle and Brafcircle were significantly up-regulated, potentially contributing to cell proliferation and tumor development. The results of this study indicated that a substantial quantity of eccDNAs was generated during both stages and regulated various biological processes, suggesting that eccDNA accumulation may correlate with the elevated risk of cancer and the emergence of multiple complications in the later stages of T2DM.

Familial hypocalciuric hypercalcemia (FHH), a rare cause of hypercalcemia, features a benign, lifelong mild-to-moderate hypercalcemia. It is often misdiagnosed as primary hyperparathyroidism, so patients may wrongly undergo parathyroidectomy. Thus, it is important to raise the suspicion of FHH before the diagnosis of primary hyperparathyroidism. Familial hypocalciuric hypercalcemia 1 (FHH1) is caused by heterozygous inactivating mutations of calcium-sensing receptor (CaSR) gene, and CaSR is a 1078-amino acid G-protein-coupled receptor and is mostly expressed in the parathyroid gland and renal tubule to maintain the homeostasis of calcium by regulating parathyroid hormone secretion and urinary calcium excretion. So far, over 150 different germline mutations of CASR in FHH1 have been reported, with 85% being missense mutations and only 3%–4% being nonsense mutations.1,2 In this study, we report a novel heterozygous nonsense mutation on the CASR (c.1799 G > A, p.Trp600∗) gene; this variant is predicted to cause an amino acid alteration from tryptophan to a premature stop codon in the extra-cellular domain, and the affected proband presented with mild hypercalcemia, low calcium to creatinine clearance ratio, and hyperglycemia with reserved insulin secreting function.

Gene therapy is considered a promising method for treating monogenic diseases. Mucopolysaccharidosis type II (MPSII) is an X-linked recessive single-gene disease mainly caused by IDS mutations. Based on the CRISPR/Cas9 gene-editing tool, a dual adeno-associated virus (AAV) system was constructed, which functions through homologous independent targeting integration (HITI). One carried saCas9 with the liver-specific TBG promoter, and the other contained a small guide RNA (sgRNA) specific target to the first codon of the mouse Alb gene and carried the CDS of the human IDS gene. Two virus vectors mixed in a specific ratio were injected into IdsX–/Y MPSII mice via the tail vein. The results showed that the expression of IDS in the liver tissue of treated MPSII mice was significantly higher than that of untreated MPSII mice. In addition, the IDS activity in gene-edited MPSII mice significantly increased, and the skeletal development of young mice also improved. The genome sequencing of the mouse liver confirmed that the human IDS donor sequence has been successfully inserted into the expected position of the mouse Alb gene. Our study provides an effective method for gene therapy of MPSII disease.

Kitlg, a pivotal protein involved in neural crest cell migration and pigmentation, harbors pathogenic variants that can lead to non-syndromic hearing loss, Waardenburg syndrome type 2, or familial progressive hyperpigmentation with or without hypopigmentation.1 Distinct KITLG mutations are associated with diverse clinical outcomes, as evidenced by the phenotypic spectrum presented in Figure S1. Not all patients with KITLG variants present with pigmentation abnormalities and hearing loss simultaneously. KITLG is known to bind to its receptor, c-Kit, activating the RAS/MAPK signaling pathway, which regulates the transcription of microphthalmia-associated transcription factor (MITF), a critical transcription factor for melanocyte generation, differentiation, and survival.2 To elucidate the mechanisms underlying hearing loss associated with Kitlg dysfunction, we generated a mouse model with a heterozygous Kitlg mutation (c.81_84 del, p.E27DfsX5) using CRISPR/Cas9 technology (Fig. 1A and B). This mutation induced a frameshift and introduced a premature stop codon. Western blotting and immunofluorescence analyses demonstrated the marked decrease in KITLG protein expression levels in heterozygous KitlgΔ/+ mice compared with wild-type (WT) controls (Fig. 1C–E). Most KitlgΔ/+ mice developed abnormal hair color, such as white hair on the belly and/or forehead (Fig. 1F; Fig. S2A). Some KitlgΔ/+ mice showed unilateral or asymmetric hearing loss (Fig. 1G; Fig. S2B). The mouse model aligns with clinical phenotypes of patients with KITLG mutation, including asymmetric or unilateral deafness and dyspigmentation.1

Chronic non-healing wounds, such as diabetic foot ulcers, represent a clinical challenge with an increasing incidence.1 A deeper understanding of the molecular mechanisms underlying wound healing is of great significance. RNA m6A modification is a widespread and important epigenetic regulatory mechanism,2 but its role in wound healing remains unclear. In this study, we found that METTL3, an RNA m6A methyltransferase, is a positive regulator of wound healing and that its low expression is closely related to chronic diabetic wounds. Mechanistically, we found that METTL3 regulates m6A modification of DNMT1 mRNA, increasing its expression and promoting keratinocyte proliferation. Additionally, we found that HNRNPA2B1 is the m6A “reader” that assists in regulating DNMT1 expression; HNRNPA2B1 can recognize m6A modifications on DNMT1 mRNA and increase its stability. Moreover, we discovered that lactate in the wound microenvironment accounts for the up-regulation of METTL3 expression during wound healing by inducing histone H3K18 lactylation. Finally, using a mouse wound model, we found that applying lactate or the lactylation “eraser” inhibitor LBH589 to the wound site promoted wound healing by up-regulating METTL3 expression. Our findings provide new targets for chronic non-healing wounds and suggest that lactylation modulation could serve as a potential therapeutic strategy for accelerating wound healing.

Although autonomic dysfunction (AutD) is a prognostic factor for Parkinson’s disease (PD), little is known regarding AutD progression-based stratification and its association with transcriptomic signatures. We examined the association between gene expression levels and risk factors according to the disease progression rate based on longitudinal changes of AutD severity in individual patients with PD. In total, 612 patients with PD with available SCales for Outcomes in Parkinson’s disease-autonomic (SCOPA-AUT) data from the Parkinson Progression Marker Initiative (PPMI) were included. A personalized hidden Markov model (HMM) was used to define the disease STATEs based on SCOPA-AUT scores. K-means clustering revealed three clusters reflecting STATE transition, with clusters 1 to 3 indicating rapid progression. Cox proportional hazard models showed that cluster 3 and gastrointestinal tract (GIT) symptoms in AutD significantly increased the risk for moderate stage PD. Furthermore, differential expression analyses revealed cluster-specific genes and molecular mechanisms associated with PD pathogenesis and GIT symptoms. Candidate molecular targets related to GIT symptoms were associated with rapid progression in patients with PD, suggesting that GIT-associated molecular targets could be used to stratify patients with PD showing different progression rates and thus facilitate personalized treatment strategies.

Dysferlinopathy affects between one person in 14 000 to one in two million.1 It is caused by mutations in the DYSF gene, a 55-exon gene on chromosome 2p13.2 Dysferlin is a 237 kDa membrane protein, which plays a role in stabilizing Ca2+ signalization and repairing the sarcolemma in skeletal muscles.3 Mutations in the DYSF gene cause a progressive muscle-wasting disease called dysferlinopathy. This disease has no approved treatment yet and induces progressive skeletal muscle atrophy. The age of onset is 20 ± 5 years, and patients notice weakness and atrophy in the calf or thigh, which evolves to include the upper limbs.4 The typical signs and symptoms are muscle wasting (27%), pain, stiffness, or cramps (13%), or pseudohypertrophy (6%), and elevated blood creatine kinase (CK) levels.4 The patients, therefore, need to walk with a cane in their thirties and become wheelchair bound in their fourth decade of life. Among the affected patients, several have point mutations (nonsense or missense). Therefore, having a mouse model with a point mutation is pertinent for developing a therapy to correct mutations (see Fig. 1).

Temporomandibular joint osteoarthritis (TMJOA) is an important subtype of temporomandibular disorders characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, chronic pain, and joint crepitus, adversely affecting the quality of life.1 Current management with non-steroidal anti-inflammatory drugs, intra-articular hyaluronic acid injections, or arthrocentesis reduces pain and inflammation to some extent, but does not repair the joint, underscoring the need for effective disease-modifying therapies.1

Orofacial cleft (OFC) is the most common congenital craniofacial disorder that significantly affects the appearance and orofacial function of patients. Although previous studies have demonstrated that rare variants are significant contributors to the genetic etiology of non-syndromic OFC (NSOFC),1 only in a limited number of cases the underlying causal genes are identified. The human Neurensin 2 (NRSN2) gene, encoding a two-transmembrane-domain protein,2 has not previously been associated with craniofacial development or malformations. In this study, we performed whole-exome sequencing (WES) and target-region sequencing (TRS) on 10 multiplex families and 138 sporadic cases with NSOFC, identifying three rare variants in the NRSN2 gene. Functional analyses in mammalian cells revealed that NRSN2 interacts with and degrades type 1 and type 2 TGF-β receptors (TβRI and TβRII) through the endosome–lysosome pathway, thereby inhibiting TGF-β signaling. In contrast, all three NRSN2 variants show an impaired capacity to degrade TβRI and TβRII, causing unrestrained TGF-β signaling. Consistently, these NRSN2 variants are less effective to induce craniofacial abnormalities in zebrafish embryos, corroborating that they are loss-of-function (LoF) mutations. Taken together, we conclude that NRSN2 variants behave as hypomorphic alleles that result in aberrant TGF-β signaling and thus NRSN2 is a novel causal gene for NSOFC in humans.

Patients with enthesitis-related arthritis (ERA) exhibit limited spinal function and clinically observable sacroiliitis,1 and they are predisposed to experiencing higher disease activity, reduced rates of disease remission, and poorer long-term outcomes compared with other subtypes of juvenile idiopathic arthritis. Nevertheless, due to the insidious onset and the subtle clinical manifestations during the early stages of the disease, achieving a timely diagnosis remains a significant challenge for children affected by ERA.2,3 Consequently, there is a pressing necessity to develop innovative, noninvasive diagnostic biomarkers with high efficacy for the screening of children with ERA. Transfer RNA (tRNA)-derived small RNAs (tsRNAs) or tRNA-derived fragments (tRFs), which are abundantly present in serum, have been reported to participate in fundamental regulatory processes and exhibit a strong association with various diseases.4 Recent research suggests that tRFs hold potential as diagnostic biomarkers and may be valuable for monitoring disease progression and determining disease prognosis.4,5 However, data on tRFs in rheumatoid arthritis and ERA remain scarce. Therefore, this study aims to investigate the expression profile of tRFs in children with ERA and assess their potential diagnostic value by examining the distribution of these small non-coding RNAs in ERA serum samples. Additionally, preliminary investigations into related biological functions were conducted using bioinformatics approaches.

Crystal-storing histiocytosis (CSH) is a rare disease characterized by an accumulation of crystalline inclusions in the cytoplasm of histiocytes. These inclusions are derived from monoclonal immunoglobulin (Ig) deposition.1 The most frequently affected organs are the bone marrow and kidney; the lung is also an affected organ due to an imaging feature identical to that of lung cancer. CSH is usually an indirect sign of malignant diseases. As a result, most patients are concurrently diagnosed with neoplastic diseases such as multiple myeloma.2 Therefore, more in-depth investigations are urgently required to clarify the underlying mechanisms of CSH. The histological characterizations of CSH have been defined; however, the cellular and molecular features of CSH remain unclear.

Secreted phosphoprotein 1 (SPP1, osteopontin) is a secreted phosphorylated glycoprotein that participates in extracellular signaling, immune regulation, and epithelial–mesenchymal transition.1,2 A recent study published in Nature demonstrated that loss of SPP1 led to depletion of mesenchymal populations, whereas its overexpression drove epithelial–mesenchymal transition and tumor aggressiveness. Mechanistically, SPP1 regulated pancreatic cancer progression through "SPP1–CD61–NF-κB–BMP2/GREM1–SPP1" feedback circuit; suggesting that SPP1 and its associated molecules (CD61, NF-κB) are potential therapeutic target(s).3

Breast cancer is the most common cancer in women, and is inherently heterogeneous at both the morphological and molecular levels.1 The evolutionarily conserved forkhead box (FOX) transcription factor family plays an essential role in various biological processes. Although the involvement of several FOX genes in breast cancer has been reported,2 limited work has been performed on the FOX gene family profiling in different subtypes of breast cancer, especially regarding the cell type-specific variation of the FOX gene family members.

Back pain related to intervertebral disc (IVD) degeneration is a common clinical problem. Inflammatory cytokines and chemokines have been found in painful/degenerative human IVDs1 and may account for some painful symptoms. The TNFAIP8 (tumor necrosis factor-α-induced protein 8) family, discovered by Chen and colleagues via genomic profiling of inflamed tissues, comprises four highly homologous mammalian proteins, designated TNFAIP8 and TIPE1-3 (TNFAIP8-like 1-3, or TIPE1-3). TNFAIP8 and TIPE2 direct leukocyte migration and fine-tune inflammation.2,3 Tnfaip8 and Tipe2 gene expression is perturbed by injury to mouse IVDs,4 suggesting that the products of these genes play a role in injury/repair responses. Furthermore, TNFAIP8 and TIPE2 loss of function ameliorated immediate proteoglycan loss and inflammation in the injured IVDs.5 Here, we examined the effects of their function loss on the IVDs in mice in which both genes were deleted. Transcriptome and morphological features of IVDs in male mice 10–12 weeks of age were analyzed. Tnfaip8/Tipe2 double knockout (dKO) mice were compared with wild type (WT) mice on the same genetic background. Four consecutive intact coccygeal IVDs (C3/4. C4/5, C5/6, and C6/7) were pooled for RNA extraction.

DNA damage and repair encompass a range of alterations and mutations in DNA, serving as a crucial mechanism for maintaining genome stability in tumor cells.1 Abnormal expression of oncogenes or tumor suppressors caused by the dysregulation of DNA damage and repair is connected to tumor proliferation, metastasis, and immune microenvironment.2 Telomere maintenance 2-interacting protein 1 (TTI1), a regulator of DNA damage and repair, is expressed in numerous organisms and is assumed to play a central role in regulating a wide spectrum of DNA damage responses, telomere maintenance, and checkpoint signaling.3 TTI1 was regarded as an oncogene and promoted tumor proliferation in colorectal cancer (CRC), providing preliminary evidence for the significance of TTI1 in CRC.4 Nevertheless, the precise role of TTI1 in CRC remains unclear. Therefore, we conducted a comprehensive investigation of TTI1 expression in CRC and its associations with clinical significance, prognosis, molecular mechanisms, tumor immunity, and potential clinical value. In summary, our study identified TTI1's role in CRC and its immune microenvironment, highlighting its significance in metastasis and immunotherapy, with meta-chlorophenylpiperazine (mCPP) identified as a potential modulator.

The ocular lens serves as an exemplary biological model for investigating mechanisms of fibrotic disease, particularly through its well-characterized epithelial–mesenchymal transition (EMT) process. In lens capsular fibrosis, lens epithelial cells (LECs) undergo phenotypic transformation mediated by the dysregulation of a complex signaling network. While multiple interconnected pathways have been implicated in this pathogenic process, current therapeutic strategies for anterior subcapsular cataract and postoperative capsular opacification remain predominantly surgical, underscoring the urgent need for targeted pharmacological interventions. SUMOylation, an essential post-translational modification system, orchestrates critical cellular processes, including gene expression, genome integrity, and cell cycle progression. Emerging evidence positions SUMOylation as a critical regulator of EMT in both fibrotic disorders and oncogenesis. Building on these insights, we hypothesized that SUMO-mediated post-transitional modifications may drive LEC transdifferentiation in lens fibrotic pathologies. Our experimental findings demonstrated that elevated global SUMOylation (SUMO1/2/3 conjugates) in human anterior subcapsular cataract specimens correlated with fibrotic progression. Sole SUMO isoform deficiency partially mitigated TGFβ2-driven EMT and injury-induced anterior subcapsular cataract. SUMO E1 overexpression enhanced LEC proliferative capacity, migration potential, and EMT progression. Pharmacological SUMO E1 inhibition (ML792) suppressed TGFβ2-induced SMAD4 SUMOylation, nuclear translocation, a critical TGFβ/SMAD signaling event. ML792 also eliminated TGFβ2-induced LEC EMT and experimental anterior subcapsular cataract. Our results establish SMAD4 SUMOylation as a pivotal molecular switch in lens fibrosis pathogenesis. Employing inhibitory drugs of SUMO conjugation in the years to come has the potential to be a novel therapeutic strategy for fibrotic cataracts.

Reduced chloride channel accessory 4 (CLCA4) levels are linked to cancer development, while its role and mechanism in cancer stem cells (CSCs) remain unclear. In this study, we discovered that decreased CLCA4 expression was evident in CD133+CD44+ colorectal CSCs and chemoresistant colorectal cancer (CRC) cells. Increased expression of CLCA4 inhibited the expression of stemness genes, reduced tumorsphere formation, suppressed the self-renewal, migratory, and invasive capabilities of colorectal CSCs in vitro, and suppressed the tumorigenicity of colorectal CSCs in vivo. Mechanistically, CLCA4 interacted with vimentin, leading to FAK pathway inactivation and subsequent suppression of CSC expansion, while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal. Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens. Increased CLCA4 expression promoted the infiltration of cytotoxic CD8+ T cells and enhanced the anti-PD-1 therapeutic efficacy. Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway, potentially reducing tumor cell stemness and evading immune surveillance. The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.

The microRNA known as miR-128-3p demonstrates widespread tissue-specific expression with its genetic locus situated on human chromosome 2 (2q21.3), and is a multifunctional regulator with tissue-specific expression patterns that critically influences cellular homeostasis and disease pathogenesis. By engaging with the 3′ untranslated region (3′ UTR) of target mRNA molecules, miR-128-3p exquisitely modulates gene expression levels, thereby orchestrating cellular proliferation, immune responses, metabolic equilibrium, and tumorigenesis. Studies on miR-128-3p in different cancers have revealed diverse expression patterns and functional roles. Intriguingly, due to its ability to target multiple genes and signaling pathways, as well as being regulated by various genes themselves, miR-128-3p exhibits both tumor-suppressive and oncogenic effects under neoplastic conditions. This review summarizes the expression patterns and complex regulatory mechanisms of miR-128-3p across various cancers. A profound understanding of the significance and regulation of miR-128-3p in cancer will drive the development of innovative therapeutic strategies using this molecule for combating human cancer and immune-related disorders.

5-Methylcytosine (5-mC) is the most prevalent DNA methylation modification in the human genome, and its abnormal patterns are strongly associated with tumor progression. Intratumoral and intertumoral DNA methylation heterogeneity (DNAmeH) primarily arises from cancer epigenome heterogeneity and the diverse cell compositions within the tumor microenvironment (TME). Furthermore, recent advancements in high-throughput sequencing and microarray technologies have facilitated the development of quantitative methods for measuring DNAmeH, enabling a more thorough exploration of the factors influencing it. Moreover, investigating various DNA methylation patterns at the single-cell level within the intricate TME sheds light on DNAmeH being driven by cellular heterogeneity. In addition, accumulating studies on the selection of methylation biomarkers in tissue or circulating DNA elucidate the cell specificity of DNA methylation, which is valuable for early cancer detection and personalized therapy. In this review, we elucidate the characteristics of intratumoral and intertumoral DNAmeH, considering DNAmeH differences across cancer types, among individual cells, and at allele-specific hemimethylation sites. Several metrics are summarized to quantitatively assess DNAmeH. We evaluate the factors that influence DNAmeH via these metrics, including the cell cycle phase, tumor mutational burden (TMB), cellular stemness, copy number variation (CNV), tumor subtype, tumor characteristics, tumor stage, state of tumor cells, hypoxia, and tumor purity. Finally, we highlight the deconvolution of TME cellular components and the application of predictive methylation biomarkers in cancer clinical research.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a significant global health threat because of its rapid evolution and high mutation rate, which limits the performance of existing molecular diagnostics. This study presents a dual-mode, aptamer-based detection platform that combines high sensitivity with mutation resilience. Using a computer-assisted X-aptamer Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach, we identified NP14, a high-affinity, dual-target DNA aptamer that specifically binds to the SARS-CoV-2 nucleocapsid (N) protein at its N-terminal domain. Analyses via molecular docking, aptamer truncation, and targeted mutagenesis revealed that NP14 interacted with both SARS-CoV-2 and SARS-CoV N proteins and identified key nucleotides C24 and G27 of the P1 region and structural determinants critical for its high-affinity binding. Building on this discovery, we engineered a dual-mode biosensing system by integrating NP14 into a multicolor dynamic light scattering-enhanced enzyme-linked aptamer-antibody assay (MD ELAAA). MD ELAAA synergistically combines two complementary detection strategies: i) non-aggregative plasmonic colorimetry for visual signal detection and ii) dynamic light scattering for ultrasensitive quantitative analysis, in which Au/Ag nanomaterials are used to amplify optical and scattering signals. This system achieves a sensitivity of 0.43 TCID50/mL, representing a 47-fold improvement over standard methods. By integrating high sensitivity, specificity, variant recognition, and dual-mode signal output, the MD ELAAA platform enables reliable detection of low-abundance SARS-CoV-2 antigens. Its robust performance supports early-stage diagnostics and high-throughput variant monitoring, establishing MD ELAAA as a robust platform for next-generation viral detection and surveillance.

Gallbladder cancer (GBC) is prone to lymph node metastasis. Lymph node (LN) metastasis is correlated with abysmal patient prognosis, but the underlying mechanism remains elusive. In this study, transcriptome sequencing of 6 paired GBC tumors and metastatic LNs was performed and identified eEF1A2 as key genes associated with GBC LN metastasis. qPCR, Western blotting and immunohistochemistry (IHC) were performed to assess the expression of eEF1A2 and relating proteins in GBC. The function of eEF1A2 and its regulators were demonstrated in different GBC cell lines as well as in xenograft models. Two independent cohorts of GBC patients were used to reveal the clinical significance. The results revealed that eEF1A2 is tightly correlated with lymph node metastasis and poor prognosis in patients with GBC. In two GBC cell lines, eEF1A2 knockdown impaired cell proliferation, migration, and invasion in vitro and inhibited tumor growth and lymph node metastasis in vivo, whereas overexpression of eEF1A2 promoted these processes. EEF1AKMT4 trimethylates eEF1A2 at K36 site in GBC and is essential for the tumor-promoting effect of eEF1A2. Mechanistically, trimethylation at the K36 site of eEF1A2 increased the GTPase activity of eEF1A2 and enhanced tumor promoting signals including ERK1/2 and AKT by promoting the ribosome total protein synthesis. In conclusion, the evolutionarily conserved EEF1AKMT4-eEF1A2K36me3-ribosome protein synthesis-tumor promoting signals axis acts as a mechanism that promotes GBC progression and may be a potential therapeutic target for GBC lymph node metastasis.

Expression quantitative trait locus (eQTL) refers to a genetic variation associated with the expression of specific genes. It has been widely applied to explain the regulatory mechanisms linking genetic variations to complex traits or diseases. Several eQTLs have been identified from tissues and single cells in individuals. Furthermore, the integration of eQTL and other omics data can be used to detect novel susceptibility genes and consequently understand the dynamic regulation of trait-associated genetic variations at the system level. Here, we review the identification methods, analysis tools, research progress, and common data resources of eQTLs, as well as their role in four typical diseases. Finally, we discussed the application fields, challenges, and future development perspectives of eQTL.

Lipid metabolic reprogramming has emerged as a hallmark in cancer research, especially that of fatty acids (FAs). It promotes the effective utilization of the limited nutrients in the tumor microenvironment (TME) by the cells and has considerably been associated with immune escape. Tumor cells exhibit enhanced FA uptake, synthesis, and oxidation for metabolic adaptation, and non-tumor cells also undergo FA metabolic remolding in the TME. Owing to the essential role of FA metabolism in TME, the associated critical enzymes may be targeted for developing novel therapeutic approaches. This review aims to comprehensively summarize the FA metabolic landscapes in various cancers and FA-related molecular changes, FA metabolic reprogramming in different cells in the TME to identify potential targets, and FA-related cell interactions and underlying mechanisms in the TME. The findings of this study may provide insights into exploring the intricate FA metabolism–TME adaptation interplay to uncover potential metabolic targets of therapeutic significance for combinatorial strategies and enhancing immunotherapy.

Gliomas are primary brain tumors known for their resistance to radiotherapy and frequent recurrence. This might result from the high heterogeneity and transcriptional plasticity of gliomas. Heat shock proteins are associated with unfavorable tumor outcomes and protect tumors from the effects of radiotherapy. However, their influence on brain tumors is not fully understood. Initial analyses of glioma patients from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases who had undergone radiotherapy identified HSP90B1 as a crucial gene affecting patient prognosis. Subsequent investigations revealed that HSP90B1 enhanced the proliferation, migration, and invasion of glioma cells. It was also found to protect glioma cells from radiotherapy-induced apoptosis. Co-immunoprecipitation (CO-IP) found that HSP90B1 directly interacted with RhoC and protected it from degradation via the ubiquitin–proteasome pathway. Rescue experiments indicated that HSP90B1 might facilitate glioma migration, invasion, and radiotherapy resistance by modulating RhoC expression. A mouse model further demonstrated that gliomas expressing high levels of HSP90B1 exhibited decreased sensitivity to radiotherapy. Overall, our research revealed that HSP90B1 significantly impacts the prognosis of glioma patients treated with radiotherapy. Additionally, HSP90B1 might enhance glioma metastasis and resistance to radiotherapy by regulating RhoC expression. This regulatory effect was achieved by the directly binding of HSP90B1 to RhoC, thereby preventing its degradation through the ubiquitin–proteasome pathway.

The TBX2 subfamily of T-box transcription factors (e.g., Tbx2, Tbx3, Tbx4, Tbx5) plays an essential role in lung development. Down-regulation of these genes in human lung adenocarcinoma suggests that these genes may be tumor-suppressive; however, because down-regulation appears to occur primarily via epigenetic change, it remains unclear if these changes causally drive tumor progression or are merely the consequence of upstream events. Herein, we developed the first multiplexed mouse model to study the impact of TBX2 subfamily loss, alongside associated signaling genes (Egr1, Chd2, Tnfaip3a, and Atf3) in Ras-driven lung cancer. Using tumor-barcoding with high-throughput barcode sequencing (TuBa-seq), a high-throughput tumor-barcoding system, we quantified the growth effects of these knockouts during early and late tumorigenesis. Chd2 knockout suppressed both tumor initiation and progression, whereas Tnfaip3 knockout enhanced tumor initiation and overall tumor growth. Tbx2 loss showed stage-specific effects on tumor development. Notably, Egr1 emerged as a strong tumor suppressor and its knockout resulted in approximately a fivefold increase in tumor size at 20 weeks (two-sample t-test, p < 0.05), exceeding the impact observed with Rb1 loss. Transcriptomic analyses of Egr1-deficient tumors suggested immune dysregulation, including heightened inflammation and potential markers of T cell exhaustion in the tumor microenvironment. These findings indicate that Egr1 may play a role in suppressing tumor growth through modulating immune dynamics, offering new insights into the interplay between tumor progression and immune regulation in lung adenocarcinoma.

Metabolic reprogramming is one of the eight hallmarks of cancer, and in lung cancer, it is notably linked to ferroptosis-related lipid metabolism. Cancer stem cells, regarded as the initiating cells of cancer, can extensively influence the tumor microenvironment (TME). Nevertheless, their role in metabolic reprogramming within lung adenocarcinoma (LUAD) remains incompletely explored. In this study, through molecular biology experiments including RNA-seq, proteomics, RNA pulldown, and PCR, we discovered a novel and intricate mechanism by which the lncRNA ROLLCSC, derived from extracellular vesicles (EVs) of LUAD stem cells, regulates the tumor TME. Mechanistically, lncRNA ROLLCSC can interact with CDC42, a GTPase protein, mediating a positive feedback loop that promotes the entry of more EVs into recipient lung cancer cells (LLC). FTO-mediated m6A demethylation enhances the stability of ROLLCSC, which is recognized by the reader protein IGF2BP2 in recipient LLC cells. Most importantly, lncRNA ROLLCSC can reshape the lipid metabolism of LLC cells by targeting ACSL4 and Slc25a11, thereby enhancing their resistance to ferroptosis. Clinically, ROLLCSC and its targets are associated with distinct tumor expression patterns and have prognostic significance. Overall, our study elucidates how the lncRNA ROLLCSC derived from cancer stem cell (CSC)-derived EVs is efficiently transported to LUAD cells, subsequently reshaping the lipid metabolism of recipient cells and enhancing their resistance to ferroptosis.

Chromosomal instability (CIN) significantly impacts the tumor progression and tumor immune microenvironment (TIME). However, few researchers have focused on CIN variables in predicting prognosis and the immune landscape of breast cancer. Through unsupervised consensus clustering, the TCGA-BRCA cohort was categorized into two clusters based on the CIN25 gene signature. After identifying the two clusters’ differentially expressed genes, we sequentially performed univariate Cox, LASSO, and multivariate Cox regression analyses to construct a 13-gene signature, termed “CIN score”. Then, the breast cancer patients were divided into low- and high-CIN score groups. The differences in survival outcome, clinicopathological parameters, TIME, and drug sensitivity between the two groups were further investigated. The high-CIN score group had unfavorable clinicopathological features and overall survival. TIME analysis indicated that the low-CIN score group had increased expression of immune checkpoint genes and infiltration of immune cells, suggesting that immunotherapy was more likely to benefit the low-CIN score group. Additionally, drug sensitivity analysis indicated the high-CIN score group has lower sensitivity to several commonly used chemotherapeutic, endocrine, and targeted agents than the low-CIN score group. The novel gene signature, CIN score, identified in our research, offers a novel tool to predict the prognosis, TIME, and drug responsiveness in breast cancer, thus providing insights into immunotherapy decision-making and contributing to the precision treatment in breast cancer.

Colorectal cancer (CRC) is a prevalent condition, with metastasis spread as the primary cause of mortality. However, MFAP2 function in CRC progression and its regulatory mechanisms in metastasis remain poorly understood. To investigate the status of MFAP2, an extensive analysis was conducted using multiple clinical databases and transcriptomic data from CRC metastasis patients’ tissues and several CRC cell lines. The efficacy of standard first-line chemotherapy drugs (5-fluorouracil, irinotecan, and oxaliplatin) were evaluated for any potential drug resistance. Virtual screening and molecular docking were used to identify potential inhibitory compounds that could be effective against CRC. Moreover, MFAP2 expression was found to be significantly higher in CMS4 CRC patients compared to those with other subtypes. This elevation in MFAP2 correlated with both tumor stromal score and tumor purity. Reducing MFAP2 expression led to a significantly decline in the functional capabilities of CRC cells and heightened their sensitivity to standard chemotherapy treatments. Results have identified MFAP2 as a key regulator in the metastasis of CRC, influencing processes like epithelial-to-mesenchymal transition through the EGFR-AKT-STAT3 signaling pathway. Therefore, MFAP2 emerges as a promising therapeutic target for anti-tumor efforts. Notable, three compounds were discovered that effectively bind and down-regulate MFAP2, which significantly impairs tumor cells migration. These findings revealed new functions of MFAP2, suggesting it plays a vital role in driving epithelial-to-mesenchymal transition, metastasis, and chemotherapy resistance in CRC. This provides a fresh perspective for developing treatment strategies. Overall, targeting MFAP2 may offer a more effective therapeutic option for CRC patients with CMS4.

Epilepsy is a highly prevalent chronic central nervous system disorder that imposes substantial societal and economic burdens. Inconsistent associations of alcohol consumption, identified as a major global health risk factor, with epilepsy risk have been reported. The aim of the present study was to assess the relationship between alcohol use and epilepsy and to identify potential underlying mechanisms, with a particular focus on the role of neutrophil extracellular traps (NETs), using an integrated multiomic approach. We assessed the global risk of alcohol consumption for epilepsy using data from the Global Burden of Disease Study 2021, and we conducted a Mendelian randomization (MR) analysis to evaluate causality. Additionally, we employed machine learning algorithms and protein–protein interaction networks to identify key genes. Our results indicate that alcohol consumption significantly contributes to the risk of epilepsy, as confirmed by MR analysis (odds ratio = 1.30, 95% confidence interval 1.06–1.60; p = 0.011). Functional enrichment analysis revealed pathways related to NET formation, whereas machine learning identified key genes such as myeloperoxidase (MPO) and neutrophil elastase. Animal and molecular experiments confirmed that acute alcohol exposure increases the susceptibility to epileptic seizures, whereas the MPO inhibitor 4-aminobenzoic acid hydrazide showed therapeutic potential for alcohol-induced epilepsy. This study provides novel insights into the role of NETs in alcohol-induced epilepsy and highlights potential therapeutic targets, thereby contributing to the development of innovative treatment strategies for epilepsy prevention and management.

Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and frequent chemoresistance. Yanghe Decoction (YHD), a traditional Chinese medicine formula, has demonstrated anti-tumor potential, but its mechanisms in OS remain unclear. In this study, we employed a network pharmacology approach to identify 67 active components and 101 OS-related targets of YHD, with core targets including AKT1, TP53, MAPK14, and CASP3, mainly enriched in the PI3K/AKT and MAPK signaling pathways. Molecular docking confirmed strong binding affinities between representative compounds and these targets. Functional experiments revealed that YHD inhibited OS cell proliferation, migration, and invasion, and promoted apoptosis by elevating intracellular reactive oxygen species levels and inducing mitochondrial dysfunction. Mechanistically, YHD suppressed the PI3K/AKT pathway while activating p38 MAPK signaling. Importantly, YHD enhanced the sensitivity of OS cells to cisplatin, demonstrating a synergistic inhibitory effect in vitro and in an orthotopic OS mouse model. These findings suggest that YHD exerts its anti-osteosarcoma effects via reactive oxygen species-mediated mitochondrial disruption and pathway modulation, and may serve as a promising adjuvant to conventional chemotherapy.

Obesity exacerbates breast cancer metastasis, yet the underlying mechanisms remain incompletely understood. Here, we identify neuregulin 4 (NRG4), a ligand of Erb-B2 receptor tyrosine kinase 4 (ERBB4), as a key regulator of metastasis, through the ERBB4-YAP1 signaling axis. Using MMTV-PyMT and 4T1 breast cancer models, we demonstrate that obesity accelerates metastasis, while NRG4, secreted by inguinal white adipose tissue (iWAT), inhibits cancer cell migration and epithelial–mesenchymal transition (EMT). Mechanistically, NRG4 activates ERBB4, producing a cleaved pERBB4 fragment that interacts with phosphorylated YAP1 (pYAP1), restricting its nuclear translocation. RNA sequencing revealed that NRG4 suppressed the transcription of Mmp9 and Mmp12, which encode matrix metalloproteinases critical for extracellular matrix remodeling and invasion. Co- immunoprecipitation and promoter assay confirmed that YAP1 bound to TEAD1 and activated MMP9/MMP12 transcription in the absence of NRG4. Importantly, recombinant NRG4 (rNRG4) reduced the growth and invasiveness of breast cancer organoids. These findings establish NRG4 as a metastasis suppressor in obesity-associated breast cancer by inhibiting the ERBB4-YAP1 pathway and down-regulating matrix metalloproteinases. Our study highlights the therapeutic potential of targeting NRG4-ERBB4 signaling to mitigate obesity-driven breast cancer progression.

As a critical metabolite in the tumor microenvironment, glutamine plays a crucial role in tumor progression, and its dual effects on promoting and inhibiting tumors have garnered increasing attention in recent years. Glutamine metabolism in tumor cells has been extensively studied; however, there is currently a lack of a comprehensive description of how it interacts with tumor stromal components in the tumor microenvironment. This review focuses on the interaction of glutamine metabolism and a range of tumor stromal components, such as macrophages, dendritic cells, T cells, fibroblasts, collagen, and blood vessels in the tumor microenvironment, as well as a summary of current prospective anti-tumor therapeutics targeting glutamine metabolism. Furthermore, this study discusses the shortcomings of mechanism research, metabolic complexity, and metabolic therapy for glutamine metabolism and proposes future research directions that are expected to provide a theoretical foundation for clinical cancer treatment strategies.

Anaplastic lymphoma kinase (ALK) plays important roles in tumorigenesis and is involved in tumor immunogenicity through various pathways. Here, we conducted a comprehensive bioinformatic and clinical analysis on the characteristics of pan-cancer ALK mutation and its association with tumor immunity and the efficacy of immune checkpoint blockade. In 2930 patients with 11 tumor types treated with immune checkpoint inhibitors, the mutation of ALK indicated favorable overall survival (hazard ratio = 0.69; 95% confidence interval, 0.57–0.83; p < 0.001). We further developed and validated a nomogram to estimate the 12-month and 24-month survival probabilities after the initiation of immunotherapy. Moreover, multi-omics analysis on both intrinsic and extrinsic immune landscapes revealed that the mutation of ALK could enrich infiltration of immune cells, enhance tumor immunogenicity, and improve immune responses. In conclusion, ALK mutation is associated with promoted cancer immunity and can be treated as a biomarker for favorable outcomes in pan-cancer immune checkpoint blockade. These results have implications for treatment decision-making and developing immunotherapy for personalized care.

DNA damage repair (DDR) genes play critical roles in maintaining genome stability. However, they are prone to genetic variation, of which pathogenic variation (PV) is a predisposing factor for high risk of cancer development in modern humans. Knowing the origin of DDR PV is critical for understanding the genetic basis and developing strategies against cancer risk for modern humans. So far, there is no consensus on the original sources of DDR PV in modern humans. We performed phylogenic analysis, and the results ruled out non-human species as the original source for the PV in modern humans through evolutionary conservation. We performed anthropological analyses by tracing the PV from modern humans in over 5000 ancient humans spanning the past 40,000 years. We observed a widespread distribution of DDR PV shared between modern and ancient humans. The shared DDR PV was predominantly found in modern non-Africans within the past 10,000 years rather than in modern Africans, highlighting that the arising time should be post the latest Out-of-Africa human migration. We also observed the rich distribution of Portuguese BRCA founder PV in Brazilian, highlighting that human admixture facilitated DDR PV transmission globally between ethnic human populations. The shorter arising time of DDR PV was further supported by the haplotyping results of DDR founder PV in multiple DDR genes and the predominant heterozygotic nature of DDR PV. Our comprehensive investigation reveals that DDR PV was mainly originated from the recent evolutionary history of modern humans, and highlights that the high cancer risk caused by DDR PV in modern humans is a by-product of the human evolution process.

RNA m6A methylation is the most common type of RNA modification, and RBM15 regulates various cellular processes by writing m6A methylation on RNA. m6A methylation mediated by RBM15 significantly affects RNA stability and translational efficiency, thereby regulating gene expression. In-depth studies have revealed that RBM15 affects the progression of various diseases by regulating the expression of multiple genes, and its m6A methylation modification process is also considered to be an effective therapeutic target. In this paper, we review the latest research progress on the regulation of m6A methylation modification of RBM15, its molecular regulation in various diseases, such as cancer and metabolic diseases, and the potential therapeutic drugs derived from it, with a view to providing therapeutic strategies for the subsequent research on RBM15 and gene therapy targeting RBM15.

Human papillomaviruses (HPV) are a major cause of several cancers, particularly cervical cancer, and remain a serious public health challenge, particularly in low-resource countries. In addition to cervical cancer, HPV is linked to vulvar, vaginal, penile, anal, and oropharyngeal cancers, especially in men. The integration of HPV into the human genome plays a key role in cancer development. This review highlights the progress in HPV vaccination and new treatment approaches for non-cervical HPV-related cancers. Current vaccines provide strong protection against cervical cancer, and next-generation vaccines aim to protect against more types of cancer-causing HPV. New immunotherapy strategies, such as DNA-based vaccines and antigen-specific immunotherapy, are being developed to more effectively target HPV-driven cancers. Promising methods, such as CRISPR/Cas9 gene editing, therapeutic vaccines, and immune checkpoint inhibitors, have shown success in early research and clinical trials. Among these, DNA vaccines stand out as cost-effective and scalable solutions for treating HPV-related tumors. This review also explores the biology of HPV-related cancers, global trends, and the latest advances in prevention and treatment. To reduce the burden of HPV-related diseases, a combined approach involving vaccination, early detection, and personalized treatment is essential. Ongoing research on therapeutic vaccines, gene therapies, and immune-based treatments could greatly improve the management of HPV-related cancers, potentially lowering their global impact. Expanding these innovations in clinical practice may significantly reduce the global burden of HPV-related malignancies.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally, often playing critical roles in various biological processes. Recent studies have highlighted the involvement of miRNAs in chondrogenesis by targeting key marker genes. Among these, miR-101a has been identified as a significant regulator, previously reported to target cyclooxygenase-2 (Cox-2, ptgs2) in various contexts. Here, we investigate the role of miR-101a in chondrocyte hypertrophy and osteoarthritis (OA) progression, focusing on its regulation of Col10a1 expression. Using multiple web-based tools (TargetScan, PicTar, miRDB, and miRCODE), we identified miR-101a as a potential regulator of Col10a1. Our in vitro experiments demonstrated that miR-101a was down-regulated during chondrocyte hypertrophy in MCT and ATDC5 cells, while Col10a1 and Cox-2 expression levels were up-regulated. Overexpression of miR-101a via mimics resulted in a significant decrease in Col10a1 and Cox-2 at both mRNA and protein levels, whereas inhibition of miR-101a led to their up-regulation. Additionally, MMP-13 protein levels were reduced upon miR-101a overexpression, with no significant changes in Sox9 and Runx2 expression. Luciferase reporter assays confirmed that Cox-2 was a direct target of miR-101a, suggesting that miR-101a indirectly regulates Col10a1 expression via Cox-2. In vivo, intra-articular injection of miR-101a mimics in a medial meniscus-induced OA mouse model resulted in decreased Col10a1 expression and reduced articular damage, supporting the protective role of miR-101a in OA progression. Our findings highlight miR-101a as a negative regulator of chondrocyte hypertrophy through Cox-2, and could be a potential target for further exploration in OA therapy.

Efficient clearance of apoptotic cells, termed efferocytosis, is essential for resolving excessive inflammation, promoting wound repair, and maintaining homeostasis. Defective clearance results in the accumulation of dead cells and other metabolites, which are responsible for chronic inflammation, nonhealing of wounds, and tissue regeneration. Emerging evidence shows that the failure to resolve inflammation and defective phagocytosis or efferocytosis increases the possibility of several diseases involving diabetic wounds and damage to the gastrointestinal mucosa in patients with inflammatory bowel disease, which is a focus of medical development and the public eye. Thus, gaining deeper insight into the molecular and cellular mechanisms of efferocytosis may be useful for inflammation resolution. This review describes the mechanism of efferocytosis and wound repair and the roles of professionals (macrophages and dendritic cells) and amateur phagocytes (e.g., epithelial cells, endothelial cells, and fibroblasts) in both processes, which may provide insight into how efferocytosis affects wound repair. Because there may be many inflammatory cells recruited to the injury area, the aim of efferocytosis is to clear these cells and release proinflammatory and anti-inflammatory mediators to promote repair. Here, we review the effects of cell-mediated efferocytosis on the timely efferocytosis of neutrophils and M1 macrophages and the relationship between M2 polarization and efferocytosis. In addition, the molecular mechanisms involved are discussed, which may further our understanding of the effects of efferocytosis. Finally, these signals also provide potential targets for tissue repair intervention.

Asthma is a complex inflammatory disease of the airways, affecting over 300 million individuals globally. Infection with enterovirus D68 (EV-D68) has been identified as a risk factor for asthma. However, the biological mechanisms of EV-D68-related asthma remain unclear. In this study, using machine learning techniques, we identified salt-inducible kinase 1 (SIK1), which plays a crucial role in associating with the asthma phenotype and EV-D68 infection. Concretely, a negative correlation between SIK1 expression and asthma risk has been revealed through Mendelian randomization. Immune infiltration analyses showed that SIK1 was negatively correlated with mast cell activity and positively correlated with T cell responses. Using weighted gene co-expression network analysis, we demonstrated SIK1's role in antiviral immune responses in asthma. Further in vitro and in vivo experiments confirmed that SIK1 was up-regulated in virus infection, and it exerted antiviral effects in various viral infections. Finally, in the asthma exacerbation model of HDM combined with EV-D68 infection, SIK1 activation effectively mitigated EV-D68-induced asthma exacerbation in mice. Taken together, our findings suggest that SIK1 serves as a protective factor in EV-D68-induced asthma by modulating antiviral immune responses, which provide new insights into potential treatments for EV-D68-induced asthma attacks.

Growth factors are bioactive molecules that play crucial roles in regulating growth, development, and disease processes, both locally and systemically. Identifying growth factors involved in bone homeostasis and targeting them is a key strategy for treating bone metabolic diseases. In this study, we observed significantly elevated serum levels of midkine (MDK) in patients with postmenopausal osteoporosis and in ovariectomized mice, based on clinical data and animal experiments. We also identified a negative correlation between MDK levels and bone mineral density. The small molecule inhibitor of MDK, iMDK, effectively mitigated estrogen deficiency-induced bone loss by promoting bone formation and inhibiting inflammatory factors. Our in vitro experiments further revealed that recombinant MDK protein dose-dependently inhibited osteogenic differentiation. Transcriptome analysis showed that recombinant MDK protein affected osteogenic differentiation through the PI3K/AKT signaling pathway. Additionally, it increased the expression of inflammatory cytokines, including IL-6, TNF-α, and IL-1β, via the NF-κB signaling pathway. These findings suggest that MDK could serve as a novel therapeutic target for postmenopausal osteoporosis, and that iMDK may be a promising therapeutic candidate.

SUMOylation, a post-translational protein modification, plays a crucial role in regulating various biological processes. Dysregulation of SUMOylation has been linked to glioblastoma progression, impacting key signaling pathways. This review summarizes the current knowledge on SUMOylation's role in glioma malignancy, highlighting its influence on cell cycle regulation, PKB/AKT signaling pathway, and microRNA expression. Our work identifies Ubc9 as a promising therapeutic target due to its role in enhancing SUMOylation, promoting glioblastoma aggressiveness, and facilitating tumor proliferation. Additionally, SAE1 correlates with glioblastoma grade and affects cell cycle regulators, while SUMOylation stabilizes CDK6, driving the G1/S transition. Targeting these pathways with inhibitors, such as topotecan and chlorogenic acid, may provide novel treatment strategies. Furthermore, SUMOylation-driven alterations in transcription factors and DNA repair mechanisms contribute to therapy resistance. Understanding these mechanisms could pave the way for innovative interventions in glioblastoma management.

Proliferation and metastasis are the core malignant characteristics in esophageal squamous cell carcinoma (ESCC) that contribute to poor prognosis. However, the mechanisms underlying cell proliferation and metastasis remain elusive. We explored the function of high-mobility group box (HMGB3) in promoting ESCC progression. HMGB3 expression in ESCC tissues and cell lines was quantified using quantitative PCR, Western blotting, and immunohistochemistry. The proliferative and migratory characteristics of ESCC cells were assessed using in vitro and in vivo assays, respectively. An RNA sequencing analysis was conducted to identify the downstream signaling pathways of HMGB3. Co-immunoprecipitation was performed to identify HMGB3-interacting proteins. HMGB3 transcriptional regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays. Elevated levels of HMGB3 were observed in both patient-derived ESCC tissues and ESCC cell lines and were correlated with poor patient prognosis. HMGB3 up-regulation promoted ESCC proliferation and metastasis, whereas HMGB3 down-regulation inhibited these processes. Mechanistically, homeodomain protein transforming growth factor beta (TGF-β)-induced factor homeobox 2 (TGIF2) transcriptionally up-regulates HMGB3. HMGB3 subsequently activates TGF-β signaling through its regulation of and interaction with toll-like receptor 3 (TLR3), ultimately promoting ESCC proliferation and metastasis. Clinically, HMGB3 expression was positively correlated with TGIF2 and TGF-β, and patients with ESCC who positively co-expressed TGIF2/HMGB3, HMGB3/TGF-β, or TGIF2/TGF-β exhibited poor prognosis. The functional role of HMGB3 in ESCC proliferation and metastasis was illustrated in our research. Targeting the TGIF2/HMGB3/TLR3/TGF-β axis has the potential to serve as a promising therapeutic approach.

The FXYD family (FXYD domain-containing ion transport regulators) proteins consist of short, single-pass transmembrane proteins that primarily regulate the Na+/K+-ATPase (NKA) pump, a key player in maintaining cellular ion homeostasis. Ranging from 60 to 160 amino acids in length, FXYD proteins display tissue-specific expression patterns and influence not only NKA activity but also the function of other ion channels, including potassium, sodium, and chloride channels. These proteins interact with NKA in diverse ways, modulating its activity to meet the specific needs of different tissues. In addition to their physiological roles, FXYD proteins are implicated in the development and progression of various diseases, such as cancer, cardiovascular disorders, renal diseases, and neurological conditions. This review offers an overview of the structures, biological functions, and molecular mechanisms through which FXYD proteins regulate ion transport. Furthermore, we explore their emerging roles in disease pathogenesis and discuss potential therapeutic strategies for targeting FXYD proteins in disease management.

Extrachromosomal circular DNA (eccDNA) is a class of circular DNA molecules that originate from and are independent of conventional chromosomes. The high specificity and stability of the circular structure of eccDNA provide new clues for its research as a disease biomarker. The recent rapid development of long-read sequencing and eccDNA identification algorithms has greatly expanded our understanding of eccDNA properties. In this review, we introduce the molecular characteristics, biological origin, and advances in detection technology of eccDNA, and mainly summarize the clinical implications of eccDNA in cancer diagnosis and prognosis, drug resistance monitoring, prenatal testing, and immune-related disease, providing support for further exploring new clinical applications of eccDNA.

The immunoproteasome represents a specialized isoform of the proteasome that is integral to the processes of antigen presentation and protein degradation. While it is primarily expressed in hematopoietic cells, its expression can also be induced in non-hematopoietic cells in response to various inflammatory stimuli. Recent research has highlighted the role of the immunoproteasome in modulating islet β-cell apoptosis and glycolipid metabolism, both of which are critical mechanisms in the pathogenesis of diabetes. Furthermore, the immunoproteasome has been demonstrated to play a significant role in the development of diabetic complications through the activation of various downstream cytokines. Investigating how the immunoproteasome is activated and involved in the pathophysiological processes of diabetes and its complications may provide innovative and promising approaches for diabetes treatment. This review aims to present a comprehensive summary of current research on the role of immunoproteasome in diabetes and its associated complications, ultimately identifying novel strategies for diabetes management and therapy.

Long non-coding RNAs (lncRNAs) are pivotal regulators of gene expression, increasingly recognized for their roles in immune responses and disease progression. Natural killer (NK) cells, essential cytotoxic lymphocytes of the innate immune system, orchestrate immune responses through cytokine secretion and direct cytotoxicity. This review elucidates the immunomodulatory functions of lncRNAs in NK cell biology and their implications in pathological conditions. LncRNAs intricately govern key NK cell processes, including development, differentiation, activation, recruitment, cytotoxic function, and immune infiltration within the tumor microenvironment. These regulatory effects are mediated through diverse mechanisms, such as transcriptional control of effector molecules, miRNA sponging, metabolic reprogramming, protein ubiquitination, and epigenetic modifications. Focusing on NK cell infiltration in tumors, we classify lncRNAs into mechanistically defined and uncharacterized groups, highlighting their roles in tumor-associated competing endogenous RNA (ceRNA) networks, epigenetic regulation, and cell death pathways. By integrating these perspectives, this review enhances our understanding of lncRNA-mediated immune regulation and underscores their potential as therapeutic targets for diseases involving NK cell dysfunction.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, with its pathogenesis tightly linked to a “pathological triad”—mitochondrial dysfunction, metabolic dysregulation, and calcium homeostasis imbalance. This triad forms a mutually reinforcing network that amplifies AD pathology, yet its precise causal relationships and clinical relevance remain incompletely understood. Here, we critically synthesize evidence from human studies, animal models, and in vitro systems to dissect how these dysfunctions interact in vivo: mitochondrial structural damage and bioenergetic failure (e.g., reduced cytochrome c oxidase activity) impair ATP production, triggering metabolic reprogramming (e.g., astrocytic Warburg-like glycolysis, lactate shuttle dysfunction) and disrupting calcium buffering via mitochondrial calcium uniporter (MCU) dysregulation. Conversely, metabolic stress (e.g., hyperglycemia-induced mitochondrial overload) and calcium overload (e.g., NMDA receptor hyperactivation) exacerbate mitochondrial damage through reactive oxygen species (ROS) bursts and mitochondrial permeability transition pore (mPTP) opening. These processes are further amplified by amyloid β-protein (Aβ) and tau pathology: Aβ oligomers directly inhibit mitochondrial respiration and activate calcium channels, while hyperphosphorylated tau disrupts mitochondrial trafficking and exacerbates metabolic enzyme dysfunction. We evaluate the clinical translatability of preclinical findings, highlighting inconsistencies (e.g., conflicting results of CoQ10 trials) and gaps (e.g., human-specific metabolic signatures). Finally, we propose a framework prioritizing multi-target therapies that disrupt the triad’s vicious cycle, emphasizing the need for biomarkers to stratify patients based on triad dysregulation patterns.

Inflammation is a double-edged sword in biology. Moderate immune responses effectively eliminate pathogens and promote tissue repair, while excessive or persistent inflammation drives acute and chronic diseases. N6-methyladenosine (m6A), a central RNA epigenetic modification, dynamically regulates inflammatory initiation, amplification, and resolution. Among m6A-binding proteins, YTHDF2—the first identified mammalian m6A reader—modulates inflammatory responses by recognizing m6A/m5C sites to control RNA stability and translation. This review reports novel insights into the role of YTHDF2 in regulating immune cell functions and inflammatory signaling pathways across various disease contexts. Specifically, it systematically summarizes the molecular mechanisms through which YTHDF2 contributes to the pathogenesis of inflammatory diseases and reviews recent advances in the development of selective therapeutic agents targeting YTHDF2. Additionally, the functional complexity of YTHDF2 within specific pathological environments is discussed, and the current challenges facing the translation of these findings into targeted therapies are outlined. This review is expected to serve as a theoretical foundation for prospective therapeutic strategies employing novel epigenomic regulation-based approaches to treat inflammatory diseases.