Post-infarction myocardial fibrosis is a pivotal pathological process leading to heart failure; however, its epitranscriptional regulatory mechanisms remain poorly defined. The role of the MYC-METTL1-HILPDA axis in this process remains unexplored. Myocardial infarction (MI) models were established in mice, and hypoxia-induced mouse cardiac fibroblasts were used. A range of molecular techniques, including qRT-PCR, Western blot, immunohistochemistry, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays, were employed to investigate the MYC-METTL1-HILPDA axis. Following MI, METTL1 and HILPDA were significantly upregulated in cardiac tissue. METTL1 stabilized HILPDA mRNA via m7G modification, thereby enhancing its protein expression. Functional studies demonstrated that HILPDA overexpression induced mitochondrial dysfunction and fibroblast activation, whereas HILPDA knockdown attenuated these effects. Furthermore, the transcription factor MYC was identified as an upstream regulator that directly binds the METTL1 promoter to activate its transcription. Crucially, HILPDA knockdown improved cardiac function, attenuated fibrosis, and reduced infarct size in mice. This study identifies the MYC-METTL1-HILPDA axis as a novel driver of post-infarction myocardial fibrosis, which promotes mitochondrial dysfunction and fibroblast activation through m7G-mediated stabilization of HILPDA mRNA. These findings provide new mechanistic insights and reveal potential therapeutic targets for preventing heart failure.

Soybeans are widely cultivated worldwide as an important source of edible vegetable oil and protein. Due to climate change, it is repeatedly exposed to various abiotic stressors in its natural habitat. Abiotic stresses such as heat, drought, and salinity severely restrict soybean productivity, yet the conserved molecular mechanisms underlying multi-stress tolerance remain poorly understood. The integrated application of machine learning and co-expression network analysis for robust biosignature and hub gene discovery remains limited. Therefore, this study aimed to identify conserved stress-responsive biosignatures and explore their evolutionary and regulatory significance. Here, we explored the transcriptional regulation of soybean under multiple abiotic stress conditions, including heat, drought, and salt. A total of 14,503 genes are differentially expressed across three stress conditions, with 466 genes common to all three. Gene Ontology and KEGG pathway analyses indicated that the meta-DEGs primarily participate in oxidative stress, hormone signaling, and metabolic pathways. Segmental duplication is the key driving force of stress response gene expansion, and most of these expansions occurred through the recent whole-genome duplication (WGD) in soybean. The 12 abiotic stress-responsive biosignatures were identified using a wedge co-expression network and machine learning (ML)- based hub genes. A deep neural network (DNN) model was constructed to validate stress biosignatures, achieving 97.39% and 76.47% prediction accuracies on the test and external validation sets, respectively. Our findings revealed conserved stress-responsive genes, key regulatory hubs, and oxidative stress as a central molecular feature governing multi-stress adaptation. The integration of artificial intelligence enabled accurate validation of biosignatures, offering valuable insights into functional genomics and genomic-assisted breeding strategies. This study offers a strong foundation for AI applications in plant breeding and supplies valuable resources for soybean genetic improvement.

This study aimed to clarify how cancer-associated fibroblast-derived exosomal circ_0067557 (CAF-exo circ_0067557) promotes epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) through BHLHE40-mediated transcriptional activation of OTUB2. CAF-derived exosomes were isolated and characterized from CRC tissues, while normal fibroblast-derived exosomes were obtained from adjacent normal tissues. The transfer of circ_0067557 was tracked using fluorescence labeling and endocytosis assays. Expression of circ_0067557, BHLHE40, OTUB2, and EMT-related markers was assessed by qRT-PCR, Western blotting, and immunofluorescence. Gain- and loss-of-function models were established to determine the biological role of circ_0067557. RNA sequencing identified OTUB2 as a key downstream target. ChIP-qPCR and dual-luciferase reporter assays were performed to verify BHLHE40 binding to the OTUB2 promoter. RIP and RNA pull-down assays confirmed the interaction between circ_0067557 and BHLHE40. Mouse xenograft and tail vein metastasis models were used to evaluate the oncogenic effects of circ_0067557 in vivo. CAF-exos successfully delivered circ_0067557 into CRC cells, significantly enhancing their proliferative, migratory, invasive, and EMT capabilities. Mechanistically, circ_0067557 interacted with and recruited BHLHE40, thereby increasing its binding to the OTUB2 promoter and promoting OTUB2 transcription. In vivo experiments further confirmed that circ_0067557 markedly enhanced tumor growth and distant metastasis through the BHLHE40/OTUB2 signaling axis. CAF-exo circ_0067557 promotes EMT, invasion, metastasis, and tumor progression in CRC by recruiting BHLHE40 and activating OTUB2 transcription. These findings reveal a novel mechanism by which the tumor microenvironment (TME) regulates cancer cell metastasis.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy characterized by an adverse outcome attributed to delayed detection, elevated recurrence rates, and resistance to chemotherapy. Identifying innovative indicators and therapeutic targets is essential for enhancing iCCA treatment. We used bioinformatics, machine learning, and experimental approaches to explore the role of ELOVL1 in iCCA. Functional enrichment analysis of DEGs was carried out utilizing GO, KEGG, GSEA, and GSVA. WGCNA and LASSO regression identified key genes linked to iCCA progression. In vitro and in vivo experiments assessed the impact of ELOVL1 on tumor growth, migration, invasion, and chemotherapy response. Western blotting and immunofluorescence were used to evaluate signaling pathways and ER stress markers. Bioinformatics analysis identified ELOVL1 as a key gene upregulated in iCCA tissues. High ELOVL1 expression correlated with poor prognosis. Functional assays showed that ELOVL1 overexpression enhanced iCCA cell proliferation, migration, invasion, and cisplatin resistance, while knockdown inhibited these effects. Mechanistically, ELOVL1 activated the PI3K/AKT/mTOR pathway and induced ER stress, promoting iCCA progression. Molecular docking studies identified ELOVL1's interaction with the PI3K inhibitor Pictilisib, suggesting a therapeutic target. ELOVL1 promotes iCCA progression by regulating the PI3K/AKT/mTOR pathway and enhancing ER stress. ELOVL1 is a potential biomarker for predicting iCCA prognosis and drug response, offering new therapeutic strategies for iCCA.

Satellite DNAs (satDNAs) are repetitive sequences that play important roles in chromosomal architecture, genome evolution, and regulation. Here, we present a comprehensive characterization of Tenebrio molitor satellitome, integrating cytogenetic mapping, in silico genome annotation, divergence profiling, screening of extrachromosomal circular DNA (eccDNA), transcription analysis across developmental stages, and phylogenetic and age analyses. SatDNAs exhibited diverse chromosomal organizations, ranging from widespread to chromosome-restricted distributions. Discrepancies between assembly-based and physical mapping highlight limitations of individual approaches and underscore the importance of their integration. Divergence landscape analyses revealed different homogenization efficiencies and turnover rates, reflecting distinct evolutionary trajectories among individual satDNAs. Phylogenetic reconstruction revealed distinct patterns which include clear species-specific clustering of monomers, mixed interspecific clustering, and dispersed topologies. Comparative analyses across insect orders enabled age estimation, identifying both ancient (≥380 MYA) and lineage-specific satDNAs, apparently restricted to T. molitor. We designed and applied an approach that enables the simultaneous detection of multiple satDNAs within the eccDNA fraction which confirmed the presence of six satDNAs in eccDNA. RNA-seq analyses revealed coordinated, stage-specific transcription of all satDNAs, with elevated expression in late male pupae and early male adults. Together, these results reveal a highly dynamic, heterogeneous, and functionally relevant satDNA landscape in T. molitor and demonstrate the importance of integrative approaches for understanding molecular mechanisms and trajectories of satDNA evolution.

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer and accounts for a large proportion of cancer-related deaths worldwide. Despite extensive research progress in recent years, the diagnosis and treatment of lung cancer remain insufficient. There is an urgent need to deepen the mechanistic understanding of lung cancer, develop early diagnostic strategies, and explore novel therapeutic targets. In this study, qRT-PCR was used to detect the expression of circPTP4A2 (circular RNA PTP4A2) in tumor and adjacent normal tissues from 50 NSCLC patients. CircPTP4A2 was significantly upregulated in tumor tissues and was closely associated with patient survival and prognosis. In vitro silencing of circPTP4A2 in NSCLC cell lines SPCA1 and H1299 significantly inhibited cell proliferation and malignant metastatic potential. Moreover, modulating the expression of miR-127-5p and SMC3 effectively reversed the phenotypic changes induced by circPTP4A2 knockdown. In conclusion, circPTP4A2 is upregulated in NSCLC and promotes tumorigenesis and progression through the miR-127-5p/SMC3 signaling axis.

Pyroptosis, a form of inflammatory programmed cell death, plays a dual role in tumor progression and anti-tumor immunity. Its comprehensive clinical and biological significance in intrahepatic cholangiocarcinoma (iCCA) remains to be elucidated. Utilizing bulk transcriptome, single-cell transcriptome, proteome, phosphoproteome, spatial transcriptomic profiling and genomic mutation data, we first identified three distinct iCCA molecular subtypes based on the expression patterns of prognostic pyroptosis-related genes (PRGs). Subsequently, we developed and validated an eight-PRG (CASP3, TIRAP, GPX4, NOD2, GSDMB, GSDMC, CASP9, IL6) prognostic signature using regression analyses. The tumor immune microenvironment was characterized, and metabolic pathways were analyzed. Single-cell RNA sequencing (scRNA-seq) of 165,236 cells from iCCA tissues was performed to investigate cellular communication. Spatial transcriptomic profiling was used to visualize cell distribution. In vitro functional assays, including TGF-β treatment, GSDMB and CDH3 knockdown, were conducted to validate mechanistic insights. The eight-PRG signature effectively stratified iCCA patients into high- and low-risk groups with significant survival differences. The high-risk subtype correlated with aggressive clinicopathological features, an immunosuppressive microenvironment, and dysregulated metabolism. scRNA-seq analysis revealed malignant epithelial cells expressing GSDMB showed heightened responsiveness to TGF-β signaling. Functional studies demonstrated that GSDMB knockdown inhibited iCCA cell proliferation, migration, and invasion, potentially through downregulation of CDH3. Further mechanistic studies validated that TGF-β promotes CDH3 transcription in a GSDMB-dependent manner. GSDMB knockdown reduced basal CDH3 expression and abolished TGF-β-induced CDH3 upregulation at both mRNA and protein levels. We established a novel and clinically applicable pyroptosis-based classifier for iCCA prognosis. Our findings hint at a possible connection of the TGF-β-GSDMB-CDH3 axis with enhanced tumor aggressiveness, providing new insights for patient risk stratification and revealing potential therapeutic targets for iCCA.

This study aimed to systematically elucidate the molecular mechanisms underlying PD-associated brain-gut dysfunction through multi-omics analyses and to evaluate the therapeutic potential of combined Deep Brain Stimulation (DBS) and Brain-Computer Interface (BCI) interventions. Transcriptomic and 16S rRNA datasets from Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA) were integrated and analyzed using DESeq2, limma, Gene Set Enrichment Analysis (GSEA), and PICRUSt2 to identify disrupted pathways and microbial functional features. In the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, four groups (Normal, MPTP, MPTP + DBS, and MPTP + DBS+BCI) were assessed using behavioral testing, Local Field Potentials (LFP) recordings, molecular assays, and histological analysis. The findings revealed synaptic damage and metabolic pathway disruptions in PD brains, accompanied by reduced abundance of Short-Chain Fatty Acid (SCFA)-producing gut microbes. Combined DBS and BCI markedly improved motor deficits, suppressed aberrant β oscillations, restored gut barrier integrity and microbial homeostasis, and reduced pathological α-synuclein (αSyn) aggregation. Collectively, these results demonstrate that DBS + BCI is associated with improvements across neural, microbial and inflammatory readouts, supporting a correlative brain-gut-immune framework.

Hepatic cold ischemia/reperfusion (I/R) injury persists during the perioperative period of liver transplantation (LT), exerting a profound impact on graft survival and being closely associated with the occurrence of early allograft dysfunction (EAD). Currently, preventive strategies against cold I/R injury remain limited. This study aimed to investigate the protective effects and underlying molecular mechanisms of caftaric acid (CA), a metabolite specifically elevated in cold-adapted hibernating animals, against hepatic cold I/R injury. The results demonstrated that CA significantly reduced the area of hepatic necrosis, attenuated liver injury, inhibited hepatocyte apoptosis, and promoted the restoration of redox homeostasis. RNA-seq analysis suggested that the MAPK pathway, particularly the activation of JNK1, plays a pivotal role in the process of cold I/R injury. Through integrated experiments including drug-target screening, molecular docking, and surface plasmon resonance (SPR), this study confirmed that CA directly binds to and interacts with JNK1, thereby regulating its phosphorylation function. Further investigations revealed that CA modulates the MAPK cascade (JNK1/FOS) to alleviate oxidative stress, mitochondrial dysfunction, and cellular apoptosis during hepatic cold I/R injury. In summary, these findings suggest that CA holds promise as a potential therapeutic strategy for ameliorating hepatic cold I/R injury, with significant clinical implications.

BCL6B has been implicated as a tumor suppressor in several solid malignancies; however, its biological function and molecular mechanisms in acute myeloid leukemia (AML) remain insufficiently defined. Public datasets were analyzed to evaluate the expression pattern, diagnostic performance, and prognostic relevance of BCL6B in AML. Epigenetic regulation was explored using decitabine treatment. Gain- and loss-of-function experiments were conducted in AML cell lines to determine the effects of BCL6B on apoptosis, cell cycle progression, and proliferation. Transcriptome sequencing, dual-luciferase reporter assays, and electrophoretic mobility shift assays (EMSA) were performed to identify and validate downstream targets. MAPK pathway alterations were examined by Western blotting. Zebrafish and nude mouse xenograft models were used for in vivo validation. BCL6B expression was significantly reduced in AML compared with normal controls and demonstrated diagnostic value across molecular subgroups. Higher BCL6B expression was associated with prolonged overall survival, indicating that BCL6B may serve as a prognostically relevant biomarker. Decitabine treatment restored BCL6B expression, suggesting that BCL6B expression may be regulated by epigenetic mechanisms. Functionally, BCL6B overexpression promoted apoptosis, induced G0/G1 cell cycle arrest, and suppressed proliferation in AML cells, whereas BCL6B knockdown exerted opposite effects. Mechanistically, GGT5 was identified as a direct transcriptional target of BCL6B. BCL6B repressed GGT5 promoter activity and counteracted GGT5-mediated pro-proliferative and anti-apoptotic phenotypes. Pathway analyses revealed that BCL6B modulated MAPK signaling in a GGT5-dependent manner, characterized by decreased ERK phosphorylation and enhanced p38/JNK activation. In vivo, BCL6B overexpression suppressed tumor growth, migration, angiogenesis, and prolonged survival. BCL6B functions as a tumor suppressor in AML by transcriptionally repressing GGT5 and modulating MAPK signaling. These findings provide mechanistic insight into BCL6B-mediated leukemogenesis and support its potential as a diagnostic biomarker and therapeutic target.