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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The invasive and metastatic potential of hepatocellular carcinoma (HCC) is tightly linked to lipid metabolic reprogramming. However, existing knowledge of the molecular regulatory network governing lipid metabolism in HCC remains incomplete. This study reveals for the first time that ADAR1 promotes HCC progression via direct binding to PPARγ mRNA to regulate lipid metabolism. Through multi-omics approaches (publicly available single-cell sequencing databases, clinical sample analysis, and cellular models), we showed that ADAR1 was aberrantly up-regulated in HCC and promoted tumor cell proliferation, migration, and invasion. The adenosine analog 8-chloroadenosine (8-Cl-Ado) dose- and time-dependently down-regulated ADAR1 expression. Transcriptomic analysis revealed that 8-Cl-Ado significantly suppressed key genes associated with cholesterol synthesis and fatty acid metabolism. Mechanistically, ADAR1 binds to PPARγ mRNA, thereby activating the PPAR signaling axis, while PPARγ knockdown significantly abrogates malignant phenotypes in HCC. Functional rescue experiments confirmed that overexpression of the ADAR1 p150 isoform rescued the tumor-suppressive phenotype induced by 8-Cl-Ado. Collectively, these findings demonstrate that 8-Cl-Ado inhibits hepatocarcinogenesis and progression by suppressing ADAR1 and subsequently regulating PPARγ-mediated lipid metabolic processes, providing novel therapeutic targets and potential intervention strategies for HCC.

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Pediatric acute myeloid leukemia (pAML) has a poorer prognosis than acute lymphoblastic leukemia, and hematopoietic stem cell transplantation (HSCT) offers curative potential in high-risk or relapsed cases. Current models cannot accurately determine which individual patients will truly benefit from HSCT, leading to overtreatment or undertreatment. We developed HSCT-64, the first parallel transcriptomic risk framework for pediatric AML, conceptually analogous to a causal G-formula approach. It comprises two treatment-specific models, aHSCT-64 for allo-HSCT recipients and nHSCT-64 for non-HSCT patients, derived from a shared 64-gene signature identified from diagnostic RNA-sequencing data, enabling individualized survival prediction under both treatment scenarios at diagnosis. Trained on 1647 cases from four COG/TARGET cohorts and validated in 233 independent patients, HSCT-64 achieved a C-index of 0.791 and AUC of 0.794 for allo-HSCT overall survival, outperforming existing clinical, cytogenetic, and leukemia stem cell-based models. Comparing risk ranks between two models identified an HSCT-benefiting subgroup patients with a predicted risk rank reduction from HSCT who experienced a 5.88-fold mortality reduction post-transplant (Hazard Ratio, HR = 0.17, P = 0.0066), while no survival gain was seen in the nonbenefiting subgroup (HR = 0.94, P = 0.899). HSCT-64 enables precise, diagnosis-time identification of pAML patients most likely to benefit from transplantation, marking a shift from high-risk-based recommendations toward individualized, transcriptome-driven decision-making.

125

Chronic liver necroinflammation induced by hepatitis B virus (HBV) infection plays a major causative role in the development of end-stage liver diseases; however, mechanisms contributing to its initiation remain unclear. Analysis of the hepatic transcriptome from HBV-replication mice or HBV-infected patients revealed that significantly down-regulated mitochondrial oxidative phosphorylation function was the salient transcriptional feature at the early stage of liver inflammation compared with the stage without liver inflammation. In cell models, persistent HBV replication-induced progressive impairment of mitochondrial respiration resulted in increased reactive oxygen species (ROS) levels. We further discovered that HBV replication-induced ROS accumulation was essential for the up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2)-associated interleukin (IL)-6/IL-8 production, mediating the activation of Janus kinase 2 (Jak2)/signal transducer and activator of transcription (Stat3) signaling, and then the expression of downstream inflammatory genes. These observations were also identified in HBV-replication mice at the early stage of liver inflammation, which exhibited elevated hepatic oxidative stress, Nrf2 expression, IL-6 and IL-8 production, and Jak2/Stat3 activation, alongside hepatic inflammatory cell infiltration. In vivo, ROS scavenging with N-acetylcysteine (NAC) mitigated these effects. Our findings underscore the critical role of ROS-dependent Jak2/Stat3 pathway activation in the occurrence of HBV-induced liver inflammation, providing new insights into the pathogenesis of chronic hepatitis B.

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ADAR1 is overexpressed in hepatocellular carcinoma (HCC) and has been linked to poor prognosis, metastasis, and recurrence; however, its precise functions and underlying mechanisms, particularly in the context of metastasis, remain inadequately elucidated. This study seeks to elucidate the functions and underlying mechanisms of the most abundantly expressed isoform of ADAR1, ADAR1p110, in the setting of HCC metastasis. In this study, hepatocyte-specific ADAR1p110 knock-in mice and engineered HCC cell lines were utilized to investigate the function of ADAR1p110 in vivo and in vitro. Genome sequencing, transcriptome sequencing, microRNA sequencing, RNA immunoprecipitation qPCR (RIP-qPCR), and RNA pull-down assays were performed to elucidate the mechanism of ADAR1p110 in HCC. We demonstrated that ADAR1p110 overexpression promotes HCC metastasis by improving the motility of HCC cells. Mechanistically, ADAR1p110 overexpression increases TUBA1A expression, which plays a crucial role in regulating HCC cell motility. At the molecular level, ADAR1p110 suppresses miR-451a biogenesis by competitively binding to pri-miR-451a, thereby preventing its cleavage by the Drosha/DGCR8 complex. Furthermore, we confirmed that TUBA1A is a direct downstream target of miR-451a.

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Hepatopulmonary syndrome (HPS) is a condition characterized by pulmonary angiogenesis and refractory hypoxemia, often seen in patients with chronic liver disease. Its unclear mechanism means that liver transplantation is the only effective therapy. Agrimoniin, a compound from Pilosa ledeb, shows potential in protecting against liver cirrhosis via anti-angiogenic and anti-glycolytic effects. This study investigates agrimoniin as a potential integrated therapy for HPS-related liver and lung dysfunction. Using transcriptome data and an ICU cohort, we analyzed the role of glycolysis in chronic liver disease progression. HPS rats were established via common bile duct ligation, and serum metabolites were measured. The oxygen consumption rate and extracellular acidification rate were also detected. Rats were treated with agrimoniin (3 mg/kg/day or 8 mg/kg/day) at the early stage of HPS. Our results showed that imbalanced oxidative phosphorylation and glycolysis correlated with chronic liver disease progression and poorer outcomes. Decreased oxygen consumption rate and increased extracellular acidification rate, as well as increased glycolysis, were observed in the HPS group. Agrimoniin treatment improved liver and lung function by inhibiting pathological angiogenesis and glycolysis. Through TCM suite analysis, molecular docking, and dynamics simulations, PGC-1α was identified as a potential target of agrimoniin. Inhibiting PGC-1α blocked agrimoniin's benefits on angiogenesis and glycolysis flux. Thus, agrimoniin may be a potential integrated therapy for HPS by activating PGC-1α to inhibit glycolysis and angiogenesis.

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Our previous preclinical study determined artesunate as a candidate drug for hepatocellular carcinoma (HCC) and identified glucosylceramidase (GBA) as one of its direct targets. This research aimed to identify the binding sites of GBA with artesunate and the potential anti-HCC mechanisms, which remain unclear. Artesunate effectively suppressed cell viability and proliferation, and enhanced apoptosis of HCC cell lines with more sensitivity in HepG2 than MHCC-97H cells. Network calculation and a series of in vivo and in vitro experimental data demonstrated that the apoptosis-related GBA-ceramide-CTSD-BID-BAX signaling was one of the key putative target pathways by which artesunate may inhibit the malignant progression of HCC. Furthermore, through integrated computational and experimental approaches, we identified Y313, E340, and N396 as critical binding residues within the GBA active site. Mutagenesis studies revealed that these residues were indispensable for the interaction, with E340R and N396R mutations exhibiting the most pronounced impairment in binding affinity and enzymatic activity, respectively. Crucially, disrupting this binding interface abolished artesunate's ability to modulate the downstream apoptotic pathway. Our findings provide the first structural and mechanistic elucidation of artesunate's target engagement with GBA, unveiling a specific signaling cascade for its anti-HCC activity and establishing a foundational framework for developing novel GBA-targeted therapies.

112

CUDC-907, referred to as Fimepinostat, functions as a dual inhibitor of PI3K and HDAC, exhibiting significant anti-tumor efficacy in a range of cancer types. However, its specific role in glioblastoma is not well understood. In this study, we investigated the effects of CUDC-907 on glioblastoma using cellular, organoid, and animal models to assess its inhibitory potential and toxicity. In vitro, we assessed glioblastoma cell proliferation, migration, invasion, and apoptosis using standard assays. glioblastoma organoids were treated to examine three-dimensional tumor growth and cellular changes. For in vivo analysis, animal models with glioblastoma received CUDC-907 to study its systemic impact and toxicity, with tumor progression closely monitored. We also tested the synergy between CUDC-907 and temozolomide to evaluate enhanced chemosensitivity. RNA sequencing was conducted to explore the fundamental molecular mechanisms involved, focusing on alterations in the cell cycle and DNA damage repair pathways. Our findings show that CUDC-907 significantly suppresses the proliferation, migration, and invasion of glioblastoma cells and promotes apoptosis, while exhibiting minimal toxicity. Additionally, CUDC-907 acts synergistically with temozolomide, a chemotherapy drug used for glioblastoma treatment, enhancing glioblastoma’s chemosensitivity to temozolomide. RNA sequencing suggests that CUDC-907 achieves its effects by influencing the glioblastoma cell cycle and inhibiting DNA damage repair. Overall, the data suggest that CUDC-907 may be a promising anti-cancer agent for glioblastoma treatment.

121

C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in aldosterone-producing adenoma, and gallium-68 pentixafor PET-CT imaging targeting CXCR4 has been utilized for subtype diagnosis in primary aldosteronism. However, the roles of CXCR4 in regulating aldosterone biosynthesis remain poorly understood. In this study, we observed a strong co-localization of aldosterone synthase (CYP11B2) and CXCR4 in aldosterone-producing adenoma and other aldosterone-producing lesions. Functional experiments in H295R cells revealed that CXCR4 overexpression significantly suppressed both aldosterone synthesis and CYP11B2 expression, whereas CXCR4 knockdown conversely enhanced aldosterone production and up-regulated CYP11B2. Mechanistically, CXCR4 inhibited aldosterone biosynthesis by up-regulating inhibitor of DNA binding (ID) proteins, which directly repressed CYP11B2 transcription. Our data demonstrate that in aldosterone-producing lesions, CXCR4 expression is consistently elevated alongside CYP11B2, indicating a potential compensatory mechanism to counteract elevated aldosterone levels.

118

Increasing evidence indicates that the galectin family played a significant role in tumor progression and is closely related to the hypoxic microenvironment within tumor tissues. However, the regulatory mechanisms behind this process are unexplored. In this study, we found that Gal-1 expression was significantly up-regulated in hepatocellular carcinoma (HCC) tissues and was closely associated with poor prognosis of patients. Intervention of Gal-1 at the cellular level significantly inhibited the malignant phenotype of hepatoma cells. For the first time, we discovered that Gal-1 was regulated by m6A modification, ALKBH5 mediated the demethylation of Gal-1 mRNA, and YTHDF2 recognized Gal-1 mRNA and altered its stability. This regulatory process was altered under hypoxic conditions, and hypoxia-inducible factors (HIFs) mediated the regulation of m6A modification in hepatoma cells by hypoxia. HIF-1α bound to the promoter region of ALKBH5 and up-regulated ALKBH5 expression, while HIF-2α bound to the promoter region of YTHDF2 and generated negative regulation. In vivo, after intervention of Gal-1, reduction of proliferative markers and inhibition of epithelial–mesenchymal transition occurred in the subcutaneous tumor. The use of LNP-siGal-1 also inhibited epithelial–mesenchymal transition.

125

Diminished ovarian reserve (DOR) is one of the leading causes of infertility, which accounts for approximately 10% of women seeking fertility treatment. However, their genetic etiology and pathogenesis are largely unknown. Recently, cyclin N-terminal domain containing 1 (CNTD1) was reported to be critical for meiosis in female mice. However, no CNTD1 mutation has been reported to be associated with reproductive diseases in humans. Here, we firstly identified CNTD1 mutation in a DOR patient. The homozygous CNTD1 splicing mutation (NM_173478.3: c.823-2A > G) was identified in a DOR patient by whole-exome sequencing. The pathogenic effect of the identified CNTD1 splicing mutation was investigated by sequencing the transcript from the patient's primary leukocytes and minigene assay. A CRISPR/Cas9-mediated Cntd1 knockout mouse line was generated to investigate its role in ovarian function. The pathogenic mechanism of the identified CNTD1 mutation was further verified by functional studies. As a result, minigene assay and direct transcript sequencing from the patient revealed that this splicing mutation induced aberrant exon skipping. The homozygous truncating mutation in CNTD1 result in the production of a C-terminally truncated protein that cannot interact with its essential meiosis partner of proline-rich protein 19 (PRR19). Cntd1 knockout mice were characterized by dramatically reduced size of ovaries and prematurely depleted follicular pools, which indicated its role in female fertility. In conclusion, this study is the first to identify CNTD1 as a novel genetic cause for DOR patients and suggests the essential role of CNTD1 in human reproduction.

136

Ferroptosis, a unique modality of regulated cell death, has become an emerging strategy for tumor therapy. Multiple cellular pathways, including redox homeostasis, iron handling, epigenetic regulation, and metabolic changes, could mediate ferroptosis. Here, we demonstrate that high expression of iron-responsive element binding protein (IRP1)/A + T rich interaction domain protein 3a (ARID3A) inhibits ferroptosis and enhances chemoresistance of pancreatic cancer cells via handling the promoter region of a ferroptosis gene, cytoglobin (CYGB). Mechanistically, the high level of iron leads to nuclear translocation of IRP1 and ARID3A, thereby mediating ARID3A binding to the promoter region of CYGB and down-regulation of chromatin accessibility. The decrease of CYGB expression results in pancreatic cancer cell resistance to ferroptosis, which makes them more resistant to chemotherapy. Clinically, high expression of IRP1 and ARID3A associates with unsatisfactory chemotherapeutic response and poor survival of patients with pancreatic cancer. Our study highlights the role of IRP1/ARID3A complex as a chemotherapy target and its potential in the combined application of ferroptosis drugs

129

Hepatocellular carcinoma is characterized by considerable molecular heterogeneity, which complicates prognostic predictions and contributes to therapeutic resistance. This study aimed to develop a molecular classification framework grounded in lipid droplet-associated genes (LDAGs) and to comprehensively elucidate their biological significance and clinical applicability in guiding personalized treatment approaches. By leveraging multi-cohort datasets, we defined LDAG-based molecular subtypes and systematically characterized their genomic alterations, metabolic features, pathway activation patterns, and therapeutic vulnerabilities. Three distinct subtypes (C1–C3) were identified according to LDAG expression patterns, each demonstrating unique clinical outcomes, mutational profiles, and metabolic reprogramming. The C1 subtype correlated with the poorest overall survival, more advanced tumor stages, and activation of pro-proliferative signaling pathways. Therapeutic vulnerabilities were subtype-dependent, with C1 showing heightened sensitivity to sorafenib. Five pivotal LDAGs (PLIN3, SET, CKAP4, RAP1B, and PISD) were implicated in the aggressive phenotype of C1, among which PLIN3 exhibited the strongest prognostic value. Functional assays confirmed that PLIN3 knockdown reduced lipid accumulation, suppressed cell proliferation and migration, and impaired tumorigenesis, whereas its overexpression promoted aggressive tumor behavior. In conclusion, our LDAG-based classification system stratifies hepatocellular carcinoma into three clinically relevant subtypes. PLIN3 emerges as a promising prognostic biomarker and therapeutic target, thereby mechanistically linking lipid metabolism to hepatocellular carcinoma progression.

131

Hepatitis B virus (HBV) infection remains a severe global public health challenge, with hepatocellular carcinoma being a primary cause of HBV-related mortality. Occult HBV infection (OBI) represents a distinct type of HBV infection that has been increasingly linked to hepatocellular carcinoma development, yet the precise molecular mechanisms underlying this association remain poorly elucidated. Although HBV pre-S deletion mutations have been shown to enhance cell proliferation and contribute to hepatocarcinogenesis, the biological functions of other types of pre-S mutations, particularly point mutations, are still mostly unexplored. In our prior studies, we identified several high-frequency pre-S point mutations from OBI blood donors. Within this research, we systematically explored the effects of these OBI-associated pre-S mutations on host cell proliferation and assessed their potential oncogenic properties. Cell proliferation assays revealed that several pre-S mutations significantly enhanced the proliferative capacity of host cells. Mechanistically, five pre-S mutations (E39K, D44N, N98T, H128R, and I161T) activated the Akt/mTOR signaling cascade, up-regulated Cyclin D1 expression, and induced G1-to-S phase cell cycle progression. Further analyses suggested that the large HBV surface protein (LHBs) likely acts as the key mediator linking pre-S mutations to signaling activation and cellular proliferation. These findings provide novel mechanistic understandings of the oncogenic potential of pre-S point mutations in hepatocarcinogenesis and may facilitate the identification of high-risk individuals within OBI populations as well as the development of treatment strategies for hepatocellular carcinoma linked to HBV.

120

Spontaneous recovery following an ischemic stroke is often limited, largely attributed to age-related decline in neuroplasticity. To overcome this, we demonstrated that ectopic expression of a cocktail of transcriptional factors (Oct4, Sox2, and Klf4, referred to as OSKTFs) reset developmental decline of epigenetic signatures in adult corticospinal neurons, without affecting their spinal projection patterns and function in controlling skilled locomotion. Corticospinal expression of OSKTFs had moderate effects on promoting collateral sprouting of the corticospinal tract axons and recovery of skilled motor function following a photothrombotic stroke. When combined with task-dependent rehabilitative training, OSKTFs treatment significantly enhanced its efficacy, suggesting that rejuvenating corticospinal neurons substantially amplifies the beneficial outcomes of rehabilitative training. Mechanistically, pharmacological perturbations and intersectional chemogenetic inhibition establish that both axon sprouting and functional recovery require mTOR activation and are mediated by newly sprouted corticospinal tract axons. Together, these findings identify a novel strategy to rejuvenate adult corticospinal neurons, which improves the otherwise modest benefits typically gained from rehabilitative training after traumatic brain injuries.

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Osteoporosis, a common orthopedic disease predominantly caused by estrogen deficiency in postmenopausal women, continues to pose a significant public health challenge due to the poorly understood molecular mechanisms. While cuproptosis has been implicated in various pathological conditions, its concrete role in the pathogenesis of osteoporosis remains unknown. Equally ambiguous remains the functional role of Sirtuin 5 (SIRT5), a mitochondrial deacylase with well-characterized involvement in aging and bone formation, in estrogen deficiency-associated osteoporosis. In the present study, we identified a novel potential Estrogen/SIRT5/Ferredoxin 1 regulatory axis that modulates both cuproptosis and the lineage commitment of mesenchymal stem cells. Using an ovariectomized mouse model, we observed that serum copper levels were reduced, whereas copper accumulation was elevated in bone tissue. Estrogen deficiency down-regulated SIRT5 expression, promoted cuproptosis, and induced obvious bone loss. Cuproptosis directly impaired the osteogenic differentiation in mesenchymal stem cells, while SIRT5 overexpression partially rescued this lineage commitment defect. Mechanistically, we showed that estrogen up-regulated SIRT5 expression, which in turn mediated Ferredoxin 1 demalonylation and enhanced its lysosomal degradation. This dual regulatory mechanism may effectively suppress cuproptosis and restore the osteogenic potential of mesenchymal stem cells. Our findings suggest that the novel Estrogen/SIRT5/FDX1 axis may function as a key regulator of bone homeostasis, and identify SIRT5 as a potential therapeutic candidate for postmenopausal osteoporosis, likely through its capacity to reduce the cuproptosis-like features of mesenchymal stem cells.

122

Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC's neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPRmt). NRC supplementation restored mitochondrial homeostasis by enhancing UPRmt and Fundc1-dependent mitophagy. Mechanistically, UPRmt inhibition abolished NRC's protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPRmt, suggesting a hierarchical regulation where UPRmt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPRmt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.

113

Advanced gastric cancer (GC) poses a significant threat to public health, leading to substantial consumption of healthcare resources due to its aggressive nature and poor prognosis. Hairy and enhancer of split 6 (Hes6), a member of the mammalian homologs of Drosophila's hairy and enhancer of split (HES) family, functions as a transcriptional cofactor owing to its unique structural features. Previous studies have indicated that Hes6 expression is elevated in several malignant tumors, contributing to the enhanced proliferation and invasion of tumor cells. However, the precise role and underlying mechanisms of Hes6 in gastric cancer initiation and progression remain poorly understood. In this study, we demonstrate that Hes6 expression is significantly up-regulated in gastric cancer tissues, with elevated levels of Hes6 correlating with poor prognosis in certain patient cohorts. Functionally, Hes6 mediates gastric cancer cells to obtain stronger proliferation, migration, and invasion abilities by activating the PI3K/AKT signaling pathway, thereby accelerating tumor progression. Moreover, Hes6 interacts with the Twist1 protein, stabilizing it and facilitating the epithelial-mesenchymal transition (EMT). Collectively, these findings offer valuable insights into the regulatory mechanisms underlying gastric cancer progression, highlighting the potential of transcriptional cofactors, such as Hes6, in PI3K/AKT signaling as promising targets for therapeutic intervention in gastric cancer.

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Accumulating data implicate Type III interferons (IFN-λs) in autoimmune disorders, prompting our exploration of their role in uveitis pathogenesis. Serum and peripheral blood mononuclear cells (PBMCs) from patients with active Vogt-Koyanagi-Harada (VKH) and active Behçet's disease (BD) were analyzed for IFN-λ expression by enzyme-linked immunosorbent assay and real-time quantitative PCR. Experimental autoimmune uveitis (EAU) was induced in IFNLR1−/− mice to evaluate disease severity, inflammatory responses, and blood-retinal barrier (BRB) integrity. RNA sequencing and bioinformatic analyses were performed to identify related genes and associated signaling pathways. IFN-λ levels were significantly elevated in active VKH and BD patients and effectively distinguished them from healthy controls. Compared with wild-type mice, IFNLR1−/− mice developed more severe EAU, characterized by increased Th1/Th17 responses, reduced Treg frequency, and disrupted blood-retinal barrier integrity, which was evidenced by decreased tight junction proteins ZO-1, Claudin-5, and Occludin. Both retinal pigment epithelium (RPE) cells from IFNLR1−/− mice and human primary retinal pigment epithelium (RPE) cells with silenced IFNLR1 secreted higher levels of interleukin (IL)-6, IL-8, IL-1β, and MCP-1, which were suppressed by recombinant IFN-λ1 and IFN-λ2. RNA sequencing revealed an enrichment of T-cell and NOD-like receptor signaling pathways in IFNLR1−/− EAU mice. Consistent with this transcriptional profile, the expression of NLRP3 and NLRP1 was upregulated in RPE cells. Knockdown of these inflammasomes reduced proinflammatory cytokine production and upregulated the tight junction proteins. These results suggest that IFN-λs may alleviate uveitis by targeting RPE cells, primarily through downregulation of NLRP1/NLRP3 inflammasome activity, thereby attenuating inflammatory responses and preserving BRB integrity.

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Precisely delineating the transcriptomic profiles of glandular epithelial (GE) cells in prostate cancer (PCa) remains a significant challenge primarily due to their diffuse and multifocal distribution. To address this, we employed spatial transcriptomics (ST) to analyze 12 PCa tissue samples from 10 patients, aiming to identify PCa progression-associated genes by analyzing expression patterns across histologically distinct regions. Transcriptomic classification via principal component analysis (PCA), uniform manifold approximation and projection (UMAP), and Louvain clustering revealed spatially resolved histological structures within each tissue section. The malignancy status, progression stages, and developmental trajectories of GE clusters were further assessed using inferred copy number variation (inferCNV), diffusion pseudotime (DPT), and partition-based graph abstraction (PAGA) analyses. Based on the preliminary characterization of developmental trajectories, pairwise comparisons of GE clusters identified key oncogenes—including TFF3, OR51E2 (PSGR), FOLH1 (PSMA), AMACR (P504S), FOS (a subunit of AP-1), SLC4A4, EGR1, NDUFB9, and H2AFJ—that are positively associated with PCa progression. Immunohistochemistry (IHC) validation further confirmed the elevated expression of SLC4A4 and H2AFJ in advanced-stage PCa. Overall, this study establishes an ST-based framework for predicting PCa progression and provides valuable insight for the identification of progression-associated genes holding promise as clinical biomarkers.

122

Glioblastoma (GBM) remains one of the most lethal primary brain tumors due to its metabolic reprogramming and highly immunosuppressive microenvironment.1 Ammonia, a byproduct of glutamine metabolism, induces a form of regulated cell death termed ammonia-induced cell death (AICD), which was implicated in the impairment of immune cell function, particularly the survival of effector CD8+ T cells, through metabolic reprogramming during immune activation.2,3 This pathway has emerged as a critical mechanism by which GBM evades immune surveillance, contributing to its resistance to immunotherapies.4 However, the role of AICD in GBM has not been systematically elucidated. Here, we performed an integrative analysis of bulk and single-cell transcriptomic data to characterize AICD-related gene expression and immune context in GBM. We constructed and validated a six-gene prognostic model (ENO2, GJB2, GRP, IL4I1, LRP2, and RPE65) that stratifies patients by survival and immune features. Spatial and single cell RNA sequencing (scRNA-seq) analyses revealed that AICD activity is enriched in mural cells and macrophages. Among independent prognostic AICD-DEGs, we identified LRP2 as a potential therapeutic target on the basis of its widespread expression and role in key biological processes (e.g., cell signaling, immune modulation, and tumor progression across cancers).5 Pan-cancer evaluation highlighted LRP2 as a promising immunometabolic target, and molecular docking identified 2-hydroxybenzylamine (2-HOBA) as a compound with strong binding to LRP2. Our findings provide a novel prognostic tool and identify LRP2 as a candidate therapeutic target, potentially restoring immune function in GBM. A schematic workflow is shown in Figure 1, while all supporting results and methods are detailed in Supplementary Materials.

123

Glioblastoma (GBM), the most aggressive primary brain tumor in adults, accounts for more than half of malignant central nervous system neoplasms. Despite maximal treatment combining surgery and chemoradiotherapy, prognosis remains poor, with a median survival of approximately 14.6 months and a five-year survival rate below 7%. A major clinical challenge lies in accurately distinguishing true tumor recurrence from post-treatment-related effects (PTREs), such as radiation necrosis, pseudoprogression, inflammation, and edema. Misclassification can delay timely interventions and compromise survival, treatment efficacy, and quality of life.1,2 To our knowledge, no previous comprehensive study has integrated blood-based transcriptomic profiling with neuroimaging to address this diagnostic and research gap. This innovation aligns with the U.S. National Institutes of Health (NIH) priorities (PAR-25-175) for integrating liquid biopsy assays and imaging for precision cancer management and responds to the FY24 GBMRP Stakeholders Meeting Summary and Gaps for GBM: “Non-invasive biomarkers, liquid biopsy and imaging strategies” reported by the U.S. Department of Defense (DoD).

134

Oliver-McFarlane syndrome (OMCS) is a rare autosomal recessive genetic disease characterized by trichomegaly, anterior pituitary hypofunction, chorioretinal degeneration and neurological manifestations. The association between this syndrome and variants in the patatin-like phospholipase domain-containing protein 6 (PNPLA6, OMIM 603197) gene was first reported by Hufnagel et al in 2015.1 The PNPLA6 gene encodes neuropathy target esterase (NTE), which plays a critical role in phosphatidylcholine metabolism, membrane phospholipid trafficking, and axonal integrity.2 PNPLA6 is expressed throughout the central nervous system and eyes during human embryonic development and is widely expressed in adult tissues. Mutations in the PNPLA6 gene alter NTE enzyme activity, thus leading to a spectrum of diseases.3 In this study, we reported a 17-year-old female patient who presented with absent secondary sexual characteristics during puberty with long and curly eyelashes, unexpectedly accompanied by marked insulin resistance and fatty liver disease. The patient was finally diagnosed with OMCS based on the whole exome sequencing (NGS) identifying novel compound heterozygous variants in the PNPLA6 gene.

137

Thyroid cancer is the most common endocrine malignancy worldwide. Although prognosis is generally favorable, young patients show more advanced and aggressive features than adults, making prognosis prediction challenging.1 In solid tumors, cancer cells interact with the surrounding environment to form the heterogeneous tumor microenvironment (TME). Among TME components, cancer-associated fibroblasts (CAFs) are key producers of the extracellular matrix and regulators of the TME.2 Single-cell RNA sequencing has revealed diverse CAF phenotypes across cancer types, arising from distinct origins and activation states. This heterogeneity underscores the need to understand CAF diversity to identify tumor-specific biomarkers for guiding personalized treatment and follow-up strategies.3 However, pan-cancer research on CAFs is limited, with very few reports on thyroid cancer.4 This study first identified CAF clusters and signature genes using pan-cancer single-cell data. CAF composition and prognostic relevance were assessed across 23 solid tumors in the TCGA pan-cancer database. Finally, age-related CAF subtypes in thyroid cancer were analyzed.Thyroid cancer is the most common endocrine malignancy worldwide. Although prognosis is generally favorable, young patients show more advanced and aggressive features than adults, making prognosis prediction challenging.1 In solid tumors, cancer cells interact with the surrounding environment to form the heterogeneous tumor microenvironment (TME). Among TME components, cancer-associated fibroblasts (CAFs) are key producers of the extracellular matrix and regulators of the TME.2 Single-cell RNA sequencing has revealed diverse CAF phenotypes across cancer types, arising from distinct origins and activation states. This heterogeneity underscores the need to understand CAF diversity to identify tumor-specific biomarkers for guiding personalized treatment and follow-up strategies.3 However, pan-cancer research on CAFs is limited, with very few reports on thyroid cancer.4 This study first identified CAF clusters and signature genes using pan-cancer single-cell data. CAF composition and prognostic relevance were assessed across 23 solid tumors in the TCGA pan-cancer database. Finally, age-related CAF subtypes in thyroid cancer were analyzed.

117

Immunotherapy has emerged as a frontline treatment for advanced esophageal squamous cell carcinoma (ESCC). Still, therapeutic resistance remains a major challenge.1 The development of robust preclinical models is critical for ESCC, as current murine-derived cell lines are limited to AKR2 and mEC25 3, which are scarce compared with human-derived counterparts. In this study, we established two primary ESCC cell lines, SYEC2 and SYEC21, derived from orthotopic tumors in C57BL/6NJ mice induced by the carcinogen 4-Nitroquinoline 1-oxide (4-NQO). Histopathological analysis confirmed their squamous cell carcinoma characteristics. Both cell lines exhibited robust proliferative and migratory capacities in vitro and demonstrated differential sensitivity to chemotherapeutic agents (5-fluorouracil, paclitaxel, cisplatin, and irinotecan). In vivo, subcutaneous injection of SYEC2 and SYEC21 can form tumors, with SYEC2 showing superior responsiveness to immunotherapy. Mechanistically, SYEC2 tumors displayed higher CD8+ T cell infiltration, lower CD4+ T cell presence, reduced major histocompatibility class I (MHC-I) expression, and elevated programmed death ligand-1 (PD-L1) levels compared with SYEC21. Whole-genome and transcriptome analyses further revealed substantial genetic heterogeneity between the two models. Collectively, we present two immunologically distinct murine ESCC models that recapitulate key features of human disease and facilitate the investigation of mechanisms underlying immunotherapy resistance.

127

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor, and its unique pathology leads to limited therapeutic benefits.1 Autophagy plays a pivotal role in cellular homeostasis, facilitating macromolecule and energy recycling and conferring protection against cellular stress. Autophagy exerts a dual role in cancer initiation and progression. In the initiation phase of tumorigenesis, it can clear pathogenic mutant proteins and prevent the accumulation of harmful substances that damage DNA, thus inhibiting tumor formation. In the cancer progression phase, autophagy may supply nutrients for synthetic metabolism in cancer cells, fostering tumor development. Furthermore, activating autophagy can enhance the sensitivity of cancer cells to chemotherapy and amplify the anti-tumor effects of chemotherapeutic agents.2,3 Therefore, profiling the function and prognostic value of autophagy-related genes (ARGs) is critical to characterize new biomarkers and prognostic risk models for HCC management. Here, we conducted a detailed investigation into the single-cell expression profiling, function, and genetic alterations of ARGs using transcriptomic data from patients within the TCGA-LIHC cohort. DNA methylation analysis uncovered novel methylation sites significantly correlated with patient survival outcomes. We then developed a prognostic model based on ARGs expression through univariate COX regression analysis. Kaplan–Meier survival analysis and receiver operating characteristic (ROC) curve revealed that the risk model could exactly predict the prognosis of HCC patients. Employing machine learning approaches, including LASSO, Random Forest, and Support Vector Machine algorithms, we identified reticulon 3 (RTN3) as a key protein with prognostic significance. Both RTN3 expression and the risk score were found to be independent indicators of immune cell infiltration within the tumor microenvironment. Furthermore, molecular docking and kinetic simulation experiments suggested ivermectin as a potential therapeutic agent targeting RTN3. Collectively, our findings reveal novel biomarkers, a robust prognostic model, and a candidate drug, offering new insights into HCC management.

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Primary central nervous system lymphoma (PCNSL), a rare extranodal non-Hodgkin lymphoma, is most commonly a diffuse large B-cell lymphoma (DLBCL). Although treated with surgery, radiotherapy, and chemotherapy, its high recurrence rate leads to an unfavorable prognosis.1 Recent advances in high-throughput molecular profiling, particularly whole-exome sequencing (WES) and genome-wide association studies (GWASs), have significantly transformed our understanding of the molecular pathogenesis of PCNSL. Recurrent somatic alterations in genes such as IGLL5, PIM1, MYD88, BTG2, PCLO, KMT2D, and BTG1 have been implicated in PCNSL oncogenesis.1,2 However, existing WES and GWAS in PCNSL have predominantly focused on older populations, leaving young patients, particularly those under 40 years of age, markedly under-represented. This data gap has created a critical barrier to understanding the full spectrum of molecular heterogeneity across age groups.

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Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease and the leading cause of disability in young people without any therapeutic treatment to date.1 The kinesin family is a molecular motor responsible for forward transport of mitochondria, RNA, proteins, and synaptic vesicles, mediating physiological and pathological processes, such as microtubule growth, axon development, and myelin degeneration.2 An abnormal number of kinesins during axonal transport may serve as biomarkers for neurodegenerative diseases. Recent studies have identified kinesin family member 13b (KIF13B), the largest family member, as an unconventional signal transduction regulator involved in myelin formation in the central and peripheral nervous systems.3 Nevertheless, whether KIF13B regulates the repair of myelin loss and its implication in the pathogenesis of MS has not been explored yet.

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Gordon Holmes syndrome (GHS) is a devastating disease characterized by neurological and reproductive dysfunction, including ataxia, dementia, and hypogonadism. Currently, patients have few positive outcomes, and little is known about disease etiology and progression at the cellular and molecular levels. Whole-genome sequencing of GHS patients identified mutations in Ring finger protein 216 (RNF216/TRIAD3), an E3 ubiquitin ligase, and OTU domain-containing protein 4 (OTUD4), a deubiquitinase.1 Patients harboring either homozygous or compound heterozygous mutations of Rnf216 alone presented both neurological and reproductive phenotypes, suggesting Rnf216 is the primary underlying genetic factor in GHS. Consequently, additional case reports have described GHS to be associated with Rnf216 mutations near the catalytically active ubiquitination region, the Ring-between-Ring (RBR) domain. The RBR domain classifies RNF216 as a specialized subset of E3 ubiquitin ligases due to its mechanism that utilizes both RING domains to coordinate protein ubiquitination. This is also observed in the RBR family member, Parkin, linked to neurodegenerative Parkinson's disease. At the molecular level, RNF216 exhibits an in vitro preference for non-canonical protein ubiquitin chain linkages, lysine-11 (K11) and K63, which are associated with signaling and DNA-damage pathways rather than proteasomal degradation via canonical K48-linked ubiquitination, suggesting that these downstream pathways may be involved in the molecular etiology of GHS2, 3, 4. In addition, analysis of human GHS-associated RNF216 mutations near the catalytically active cysteine in the RBR domain showed that these mutations completely abolished E3 ubiquitin ligase activity in vitro, rendering RNF216 catalytically inactive.2,4 Our group was first to report Rnf216 gene knockout (Rnf216 KO) in mice, which resulted in disrupted spermatogenesis and male infertility, highlighting the essential role of RNF216 in male reproduction.5 However, the key molecular mechanism underlying RNF216-related GHS and its associated reproductive dysfunction remains unclear. To gain a better understanding of the human GHS RNF216 mutation in male reproduction, we generated a novel transgenic mouse model harboring the E3 ubiquitin ligase-inactivating mutation observed in GHS patients.

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The development and progression of cancer involve complex interactions among multiple signaling pathways and molecular mechanisms.1 The identification and characterization of novel biomarkers with broad clinical utility are essential for elucidating cancer mechanisms. Coiled-coil α-helical rod protein 1 (CCHCR1), identified as a centrosome-associated molecule localized to P-bodies and centrosomes, has been found to be involved in cytoskeletal organization, cell proliferation, and differentiation.2,3 Recent studies suggest its potential oncogenic role in certain cancers; however, its function across a broad range of malignancies and the underlying molecular mechanisms have not been fully characterized. In this study, we conducted an integrated analysis of CCHCR1 in pan-cancers and thoroughly investigated its oncogenic mechanisms both in vitro and in vivo.

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Renal dysplasia is defined by defective ureteric branching morphogenesis and nephrogenesis, which is the leading cause of renal failure in children. Currently, there is no effective therapeutic strategy.1 It is generally categorized as the complete absence of the kidneys, small kidneys (unilateral or bilateral) with or without normal renal architecture, and massive multicystic kidneys at the gross level.2 However, the detailed phenotypic features and regulatory mechanisms involved in the genesis of renal dysplasia remain poorly understood. Thus far, approximately 70 genes, including transcription factors (Six1 and Pax2) and growth factors (GDF11 and FGF), have been reported to play important roles in human renal dysplasia.3 In this study, we revealed the new genetic role of minichromosome maintenance complex component 4 (MCM4), highlighting the importance of MCM4 in maintaining tubular cell structure and kidney function. Deletion of MCM4 in kidney tubules resulted in fewer nephrons and a severely dysmorphic and dysplastic tubule system. MCM4 may be extended to identified as a new genetic target in renal development and provide valuable insights into potential therapeutic strategies and precision medicine.

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Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high morbidity and mortality, particularly in patients requiring surgery or intensive care.1 A hallmark of ARDS is acute pulmonary inflammation that progresses to systemic inflammation. MicroRNAs (miRNAs) are integral regulators of gene expression, and their dysregulation in immune cells is intricately linked to inflammatory responses.2,3 Among them, miR-27a has garnered attention for roles in oncogenesis, chemoresistance, and inflammation.4 However, their expression pattern across different tissues and immune cell populations during ARDS-associated organ injury remains underexplored, and genetic tools to study their function in vivo are lacking. Here, we profiled miR-27a-3p and miR-27a-5p and demonstrated that miR-27a-3p had higher expression than miR-27a-5p in most organs. However, this ratio was reversed in myeloid-derived cells, where miR-27a-5p was particularly enriched. We further examined their regulation during endotoxin-induced lung injury and found that miR-27a-5p is strongly induced under inflammatory stress in both pulmonary and non-pulmonary organs, suggesting a role in systemic immune regulation. To investigate its tissue-specific involvement, we generated a conditional knockout mouse line enabling myeloid-specific deletion of miR-27a. It resulted in altered hematopoiesis and elevated basal cytokine expression, underscoring the contribution of myeloid-derived miR-27a to inflammatory homeostasis.

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Osteoarthritis (OA), a chronic degenerative joint disorder, is a primary cause of disability, affecting over 520 million people globally.1 While age-standardized rates (ASRs) for incidence, prevalence, and disability-adjusted life years (DALYs) are projected to decline slightly annually from 2020 to 2035, absolute case numbers will continue to rise, underscoring OA as a persistent public health challenge.2 Therefore, identification of therapeutic targets for OA is of significant clinical importance. The current research on OA drug targets is predominantly confined to blood and single-omics analysis, with a notable absence of integrated, cross-tissue, and multi-omics validation.3, 4, 5 Herein, our objective is to systematically identify tissue-specific priority drug targets for OA through a comprehensive cross-tissue and multi-omics analysis framework.

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NLR family pyrin domain-containing 3 (Nlrp3) inflammasome, known for its role in mediating inflammatory responses at cellular and tissue levels, has now emerged as a pivotal mediator in the pathogenesis of metabolic disorders.1 In models of ageing and obesity-related metabolic disorders, Nlrp3 manipulation has been demonstrated to correlate with the maintenance of glucose metabolic homeostasis.2,3 Both systemic and liver-specific Nlrp3 knockout mouse models demonstrate a critical role of Nlrp3 in the regulation of the hepatic insulin signaling pathway.4 Given the liver's pivotal role in glucose homeostasis, it is plausible that Nlrp3 contributes to the modulation of hepatic glucose metabolism; however, a comprehensive mapping of this metabolic network remains incompletely characterized. In a different context, Nlrp3-specific inhibitors have been demonstrated to attenuate methionine and choline-deficient diet (MCD)-induced hepatic fibrosis and inflammation,5 whether genetic ablation of Nlrp3 confers protective effects remains to be elucidated. Therefore, this study was conducted to investigate the role of Nlrp3 in hepatic glucose metabolism, and additionally, to evaluate its potential protective effects in an MCD-induced mouse model.

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Pancreatic cancer (PC) is a highly lethal malignancy with a poor prognosis.1 Long noncoding RNAs (lncRNAs), particularly natural antisense transcripts, play critical roles in regulating gene expression and tumorigenesis.2 Antisense lncRNAs modulate tumor progression by regulating the expression of their corresponding sense strands and activating downstream signaling pathways.3, 4, 5 However, the specific mechanism of their positive-sense action and the molecular mechanisms of their tumor-promoting or tumor-suppressive effects remain undefined. In this study, we demonstrated that SERTAD4-AS1 inhibited the proliferation and invasion of PC cells through the Notch1 signaling pathway. Mechanistically, SERTAD4-AS1 stabilized SERTAD4 mRNA by forming a double-stranded RNA structure with SERTAD4. Moreover, SERTAD4-AS1 directly bound to the NONO protein and prevented the transcriptional repression of SERTAD4 by NONO. Collectively, these results suggested the regulatory mechanism of SERTAD4-AS1 and uncovered the importance of the SERTAD4-AS1/NONO/SERTAD4/Notch1 pathway in PC. These findings also indicated that SERTAD4-AS1 may serve as a therapeutic target for PC treatment.

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Congenital tufting enteropathy (CTE), which is a rare inherited intractable diarrhea of infancy and is characterized by intestinal epithelial cell (IEC) dysplasia and villus tufting, is mostly caused by the loss-of-function mutation of EpCAM.1 However, the mechanisms of EpCAM on regulating the development and morphology of the intestinal epithelium remain unclear. The expression level of EpCAM is higher in the crypts than the villi of small intestines,1 indicating that it plays important roles in the intestinal stem cells (ISCs). We recently found that EpCAM maintains the longevity of ISCs.2 However, the functions of EpCAM in the differentiation and division of ISCs still need to be explored. Here, we performed single-cell RNA sequencing (scRNA-seq) to compare the developmental potential of IECs from wild type (WT), EpCAM+/− and EpCAM−/− embryos at the E18.5 stage and uncovered the pathological mechanism of CTE that EpCAM deficiency might elevate the activation of EGFR in the ISCs and transit-amplifying (TA) cells to cause the tufting intestinal epithelium and the immaturity of IECs.

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Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis.1,2 Despite recent advances in surgical techniques and systemic therapies, the molecular drivers of ICC progression remain incompletely understood. Coiled-coil domain-containing proteins (CCDCs) are increasingly recognized for their roles in tumor biology. Among them, CCDC178 has emerged as a candidate oncogene in certain cancers, but its role in ICC has not been previously elucidated.3 In this study, we identify CCDC178 as a key oncogenic regulator in ICC and reveal its mechanistic function through leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4)-dependent signaling and immune modulation.

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Rho GTPase-activating protein 21 (ARHGAP21) (MIM: 609870) encodes a member of the RhoGAP family that is predominantly expressed in the brain (https://www.proteinatlas.org/). The ARHGAP21 protein localizes to the Golgi apparatus via interaction with ADP-ribosylation factor 1 (ARF1) protein, where it inhibits cell division cycle 42 (CDC42) activity to regulate the actin-related protein complex 2/3 (ARP2/3) complex and actin dynamics. These processes are essential for maintaining Golgi structure and cytoskeletal organization, which are crucial for cell–cell junctions and adhesion.1 Previous studies have shown that variants in ARHGAP21, ARF1, and CDC42 are associated with neurodevelopmental disorders (NDDs) and seizures/epilepsies (https://www.hgmd.cf.ac.uk/). While ARF1 (MIM: 103180) and CDC42 (MIM: 116952) are established causative genes, the pathogenic relevance of ARHGAP21 variants in epilepsy/NDDs remains to be elucidated.

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Cisplatin is widely employed in the treatment of gastric cancer (GC). However, the resistance mechanisms exhibited by GC cells often result in suboptimal clinical outcomes associated with cisplatin therapy. Autophagy, a self-degradative cellular process, plays a complex dual role in regulating tumor cell death and survival. In recent years, significant attention has been directed toward the relationship between autophagy and cisplatin resistance in GC, fostering the development of various autophagy-related drugs and potential targets aimed at enhancing the sensitivity of GC cells to cisplatin. Nevertheless, a comprehensive analysis of the correlations among relevant studies is still lacking. This review synthesizes recent research examining the impact of autophagy on cisplatin resistance in GC cells, with particular emphasis on existing drugs and potential therapeutic drugs/targets. It briefly explores the fundamental processes of autophagy and clarifies the relationship between autophagy mechanisms and GC. Furthermore, it summarizes the available drugs and potential candidates that can either enhance or inhibit autophagy, thereby improving GC cell sensitivity to cisplatin, alongside their underlying mechanisms. Additionally, it consolidates pertinent research findings to present a more thorough understanding of the intricate relationships between autophagy and cisplatin resistance in GC cells. We hope this review will encourage researchers to investigate novel mechanisms of cisplatin resistance in GC cells, discover new targeted therapies, and propose innovative strategies to tackle this challenge.

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Infection with hepatitis B virus (HBV) remains a severe concern to public health, with roughly 292 million people worldwide suffering from the chronic form of the disease, for which there is no cure. Chronic HBV infections frequently lead to hepatocellular carcinoma (HCC), one of the world's leading causes of cancer-related deaths. Although the process of hepatocarcinogenesis is complex and not fully understood, various studies have identified numerous long non-coding RNAs (lncRNAs) as contributing to the formation of HCC. These host-derived lncRNAs are frequently dysregulated as a result of viral infection. Numerous lncRNAs have been linked to HBV carcinogenesis and replication, particularly those that are dysregulated in HBV-associated HCC. HBV X protein regulates the majority of these dysregulated lncRNAs. Certain lncRNAs have been found to exert regulatory functions in HBV replication and carcinogenesis. The prognosis for HCC remains poor, and early detection of novel tumor markers is critical for effective HCC therapy. Understanding the biological activities and regulatory mechanisms of HCC-associated lncRNAs will aid in disease diagnosis and therapy and help elucidate the disease etiology. In HBV-related HCC, certain dysregulated lncRNAs may develop into biomarkers for early detection or potential targets for HCC treatment. This review provides a brief overview of the recent findings on lncRNAs in HBV with a focus on current developments. We also investigated the possible relevance of dysregulated lncRNAs in HCC as biomarkers for diagnosis and treatment and assessed their carcinogenic and tumor-suppressive effects.

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The emerging focus on epigenetic regulation in cancer biology has unveiled the significant role of CXorf67, a protein encoded by a gene on the X chromosome. CXorf67 interacts with core components of PRC2, namely EZH2 and SUZ12, thereby influencing histone modifications like H3K27me3. Research indicates that CXorf67 is overexpressed in specific malignancies, including posterior fossa ependymomas, diffuse midline glioma, endometrial stromal sarcoma, non-small cell lung cancer, and Merkel cell carcinoma. In posterior fossa ependymomas and diffuse midline glioma, CXorf67 mimics the oncogenic histone H3K27M, inhibiting PRC2 function and altering chromatin states. In endometrial stromal sarcoma, CXorf67 forms fusion genes with MBTD1, potentially disrupting polycomb group (PcG) functions. Additionally, CXorf67's interaction with PALB2 affects the BRCA1-PALB2-BRCA2 complex, influencing DNA repair mechanisms. These findings highlight CXorf67's dual role in epigenetic regulation and DNA damage response, suggesting its potential as a therapeutic target. However, further research is needed to explore its functions in other cancers and clarify its molecular mechanisms. Our review synthesizes current knowledge on CXorf67's biological significance, particularly in epigenetics and DNA damage, and its implications in oncogenesis.

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Castration-resistant prostate cancer represents a critical clinical challenge due to its propensity for resistance to conventional therapies and limited treatment efficacy. Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation. It holds therapeutic potential and can be induced by glutathione peroxidase 4 (GPX4) inhibition, glutathione depletion, or iron overload using compounds such as RSL3 and Erastin. These approaches show promise in overcoming drug resistance and enabling synergistic effects with anti-androgen therapy, chemotherapy, and immunotherapy. This review systematically summarizes the core regulatory networks of ferroptosis in prostate cancer (such as the PI3K–AKT–mTOR, Hippo/YAP, PGE2, and their downstream pathways), summarizes combination treatment strategies and clinical trial progress, proposes a three-pronged translational framework of “ferroptosis regulatory network–biomarkers–precision therapy”, and discusses the challenges it faces in terms of drug resistance, targeting accuracy, and clinical translation. These insights aim to accelerate biomarker discovery, optimization of multimodal combination regimens, and the translation of ferroptosis from fundamental research into transformative therapeutic interventions.

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X chromosome inactivation (XCI) is a crucial epigenetic mechanism that balances X-linked gene expression in females via random silencing of one X chromosome. Skewed XCI—non-random inactivation favoring one allele—impacts disease penetrance in X-linked disorders. In heterozygous females, phenotypic severity correlates with XCI skewing degree. Accurate XCI quantification is critical for predicting clinical variability and improving risk assessment in X-linked mutation carriers. The X inactivation-specific transcript (Xist) gene drives XCI initiation through its long non-coding RNA (lncRNA) that recruits polycomb repressive complexes 2 (PRC2) to establish stable heterochromatin. Bracingly, emerging therapies leveraging XCI reactivation (e.g., Xist RNA inhibition, Xist RNA epigenetic modification) show preclinical potential to rescue silenced alleles, advancing treatment strategies for X-linked diseases. This review synthesizes XCI mechanisms, current skewing detection methods, and therapeutic developments, providing a roadmap for clinical translation of XCI-targeted interventions.

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N6-methyladenosine (m6A) modification is a crucial epigenetic mechanism that is widely expressed across various tissues and biological systems. It regulates gene expression by influencing the stability and translation of messenger RNAs, thereby affecting key physiological processes such as cell division, proliferation, and apoptosis. m6A modification plays an essential role in maintaining normal physiological functions and in the pathogenesis of a variety of diseases. Recent studies have highlighted the involvement of m6A in the development of the nervous system and its contribution to neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. However, research on the involvement of m6A in nervous system disorders induced by toxic substances remains limited. This review provides an updated overview of the role of m6A in neural development, with a particular focus on exploring the potential mechanisms by which m6A contributes to toxicant-related neurodegeneration diseases.

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Global aging is increasing, and both aging and age-related diseases have emerged as significant public health challenges. According to previous literature, aging is characterized by multiple hallmarks, such as systemic inflammation, telomere depletion, mitochondrial dysfunction, and others. Obesity is a chronic and complex disease. Notably, obesity can accelerate the aging process and shares several similar features with aging. Therefore, this review systematically summarizes the relationship between obesity and aging, and discusses the great potential of anti-obesity therapies in combating aging and aging-related diseases.

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Tuft cells are rare, chemosensory epithelial cells present in various tissues, including the respiratory and gastrointestinal tracts. Recent studies have revealed their significant role in cancer biology, particularly through the expression of the transcription factor POU2F3, which serves as a master regulator of tuft cell lineage. In several cancer types, including small cell lung cancer, gastric cancer, and breast cancer, POU2F3 expression defines a distinct molecular subtype termed “tuft cell-like” tumors. These tumors exhibit unique transcriptional programs and altered tumor-immune interactions, contributing to their distinct therapeutic sensitivities. In this review, we first analyze the expression patterns of POU2F3 across cancer types using the TCGA datasets, revealing differential expression profiles and supporting the classification of tuft cell-like subtypes. We further explore cancer-type-specific signaling pathways regulating tuft cell differentiation and function, such as IL-25, acetylcholine, and taste receptor-related pathways. Finally, we propose that tuft cell-like signatures may serve as promising biomarkers for diagnosis, prognosis, and treatment stratification. Understanding the tuft cell-like–POU2F3 axis could open new avenues for targeted therapies in lineage-defined cancers.

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in GLA gene, which result in deficient α-galactosidase A activity, leading to intralysosomal accumulation of metabolic substrates and multi-organ injury. Due to the heterogeneity of clinical phenotypes and limitations of current diagnostic modalities, the diagnosis of FD remains challenging. Enzyme replacement therapy is the cornerstone of FD treatment. However, this therapy cannot fully reverse pre-existing organ damage, and patients will still face an unfavorable prognosis. The mechanisms of organ injury in FD cannot fully explain reduced enzyme activity alone and therefore warrant further elucidation. In recent years, omics, including transcriptomics, proteomics, and metabolomics, have demonstrated great potential for elucidating FD pathophysiology, identifying novel biomarkers, and uncovering therapeutic targets. This review presents the pathophysiological mechanisms of FD in its principal target organs and summarizes recent advances in omics applied to its primary target organs, chiefly the kidney and heart. Omics-based investigations hold promise for advancing precision medicine in FD, offering new avenues for early diagnosis and personalized therapy.

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Piezo ion channels, notably Piezo1 and Piezo2, are key mechanosensors that transduce mechanical forces into intracellular signals, playing indispensable roles in digestive physiology. These channels regulate essential functions such as intestinal motility, epithelial barrier integrity, bile secretion, and host–microbiota balance. Emerging evidence links aberrant Piezo signaling to a wide range of gastrointestinal disorders, including functional bowel diseases, inflammatory conditions, and digestive cancers. However, translating these insights into therapeutic applications remains challenging. Most current findings are derived from animal models or in vitro studies, which do not fully recapitulate human tissue complexity. Advanced human-relevant platforms, such as organoids and organ-on-a-chip systems, are needed to bridge this translational gap. Furthermore, Piezo1 and Piezo2 play both overlapping and distinct roles in gastrointestinal pathophysiology, necessitating selective modulation strategies. While Piezo1 promotes processes such as epithelial remodeling and tumor invasion via pathways like RhoA/ROCK and YAP/TAZ, Piezo2 is more associated with sensory neuron activity, immune modulation, and tumor aggressiveness. The lack of specific agonists and inhibitors, especially for Piezo2, further limits its clinical translation. Lastly, Piezo channels are deeply integrated into complex molecular networks involving focal adhesions, cytoskeletal dynamics, and transcriptional regulation. This review synthesizes current advances in the mechanobiology of Piezo channels within the digestive system and highlights future directions for mechanistically-informed, Piezo-targeted therapies.

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Osteoarthritis (OA) is a degenerative joint disease driven by a complex interplay of inflammation, extracellular matrix degradation, subchondral bone remodeling, and chronic pain. Purinergic signaling has emerged as a key regulator of OA pathogenesis, where dysregulated extracellular nucleotide-mediated P2 receptor activation and impaired adenosine-mediated P1 receptor signaling disrupt joint homeostasis. Excessive activation of P2X and P2Y receptors amplifies inflammatory cascades, promotes chondrocyte apoptosis, enhances matrix metalloproteinase activity, and sensitizes nociceptive pathways, while reduced P1 receptor signaling, particularly via A2A and A3, compromises anti-inflammatory and chondroprotective mechanisms. Additionally, disruptions in extracellular nucleotide metabolism exacerbate disease progression by perpetuating synovial fibrosis, cartilage destruction, and persistent pain. This review provides a mechanistic overview of purinergic receptor dysregulation in OA, detailing its roles in synovial inflammation, cartilage homeostasis, subchondral bone remodeling, and pain transmission. Furthermore, this review explores emerging therapeutic strategies targeting purinergic receptors, particularly P2 receptor antagonists and P1 receptor agonists, which are being developed as selective ligands to restore joint homeostasis and attenuate disease progression. Understanding the intricate molecular crosstalk between the P2 and P1 receptor pathways will be critical for the development of precision therapies aimed at modifying OA pathophysiology and improving clinical outcomes.

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Ménière’s disease is a prevalent chronic condition that triggers a range of vestibular and auditory symptoms. Despite significant advances in mechanisms such as genetic susceptibility, immunity, and allergy, a clear understanding of its core pathophysiology has not been established, and a consistent theoretical framework is still lacking. In this review, we discuss the advantages and disadvantages of recent animal models of Ménière’s disease, advances in mechanistic studies on Ménière’s disease, and current treatment approaches. This discussion aims to provide a reference for future research on the mechanisms of Ménière’s disease.

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T cell exhaustion is a state of T cell dysfunction resulting from persistent antigenic stimulation, characterized primarily by the high expression of inhibitory receptors, metabolic reprogramming, and epigenetic remodeling. T cell exhaustion is closely associated with immune responses in chronic infections, tumor escape, and organ transplantation. In transplantation immunology, T cell exhaustion plays a dual role: moderate exhaustion can promote immune tolerance and reduce graft rejection, while excessive exhaustion may weaken the defensive capabilities of the immune system, increasing the risk of infection and tumorigenesis. Therefore, effective regulation of T-cell exhaustion has become a crucial issue in the field of immunotherapy. Epigenetic or metabolic interventions may offer novel insights for achieving graft-specific tolerance. Further studies can focus on precise modulation of T-cell exhaustion through metabolic reprogramming, epigenetic regulation, and immune checkpoint inhibition, ultimately enhancing the efficacy of transplantation immunology and immunotherapy. This review focuses on the molecular phenotype, metabolic patterns, and mechanisms of epigenetic changes in exhausted T cells. It also explores the research progress of T cell exhaustion in organ transplantation. Furthermore, the review introduces strategies to induce T cell exhaustion, discussing how these strategies can effectively reduce the side effects of immunosuppressive therapy and promote graft tolerance.

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Diabetes mellitus, a chronic metabolic condition, is marked by ongoing hyperglycemia and poses an increasing global health issue. Beyond its recognized contribution to the development of cardiovascular diseases and kidney problems, diabetes can profoundly impact immune system functions. Recent developments in immunology have revealed trained immunity as a mechanism through which innate immune cells experience enduring functional modifications following their first encounter with specific stimuli. This review compiles the latest evidence concerning the role of trained immunity in the development of diabetes and its complications. Moreover, it discusses emerging therapeutic opportunities that may arise from modulating trained immunity pathways. This review emphasizes the complex relationship between metabolic dysregulation and innate immune memory by synthesizing results from various studies. It proposes that focusing on trained immunity may provide innovative approaches for managing diabetes and its related complications.

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The therapeutic potential of stem cell therapy critically depends on precise epigenetic regulation mediated by PIWI/piRNA complexes. This review synthesizes current literature to analyze the structure, interaction mechanisms, and epigenetic functions of PIWI proteins and their associated piRNAs (24–32 nt non-coding RNAs), with emphasis on stem cell therapy and disease modeling applications. PIWI/piRNA complexes critically regulate transcriptional control, chromatin remodeling, and stem cell plasticity. These complexes maintain stemness while promoting differentiation, serving as key biomarkers and therapeutic targets in cancers and skeletal disorders. However, translational challenges regarding specificity, delivery stability, and safety profiles persist. Advancing PIWI/piRNA-based therapeutics requires innovative technologies and expanded clinical validation to develop safe, targeted stem cell treatments for diverse pathologies.

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