Biology Direct最新文献

{"title":"ELOVL1 promotes the progression of intrahepatic cholangiocarcinoma by enhancing endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway.","authors":"Weigen Wu, Danhong Zhan, Yihui Gao, Yang Jiang, Qiguang Pang, Yuchen Pei, Junlong Wang, Yao Li, Yuqing Wang, Shayuanzi Huang, Ruizhi Wang, Meifang He, Wei Chen","doi":"10.1186/s13062-026-00790-8","DOIUrl":"https://doi.org/10.1186/s13062-026-00790-8","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative satellitomics reveals distinct patterns of organization, transcription and evolution of satellite DNAs in Tenebrio molitor.","authors":"Patrik Majcen, Antonio Sermek, Đurđica Ugarković, Brenda Oppert, Miroslav Plohl, Eva Šatović-Vukšić","doi":"10.1186/s13062-026-00808-1","DOIUrl":"https://doi.org/10.1186/s13062-026-00808-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pyroptosis-related molecular signature stratifies prognosis and highlights GSDMB-mediated malignancy in intrahepatic cholangiocarcinoma.","authors":"Binhan Zhao, Yongji Zhu, Ziyang Jin, Xiang Li, Kainan Lin, Yifan Wang, Yunkun Lu, Wen Hua","doi":"10.1186/s13062-026-00824-1","DOIUrl":"https://doi.org/10.1186/s13062-026-00824-1","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircPTP4A2 (hsa_circ_0007364) facilitates non-small cell lung cancer progression by regulating miR-127-5p/SMC3.","authors":"Yali Feng, Jiang Hong, Changgang Yang, Chun Cheng, Yujie Xue, Jiaqi Zhang, Yu Lu, Xiang Cao, Gengxi Jiang, Xiaodan Chong","doi":"10.1186/s13062-026-00815-2","DOIUrl":"https://doi.org/10.1186/s13062-026-00815-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis of deep brain stimulation associated with brain-gut axis modulation and symptom amelioration in a Parkinson's disease mouse model.","authors":"Ye Song, Changxin Yang, Jie Tu, Jiaojiao Dong, Xiao Zhang","doi":"10.1186/s13062-026-00778-4","DOIUrl":"https://doi.org/10.1186/s13062-026-00778-4","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of Caftaric Acid against hepatic cold ischemia/reperfusion injury in the liver.","authors":"Ying Zhu, Hao Li, Minghao Li, Wenzheng Ruan, Mingjie Ding, Guohua You, Lele Zhang, Wenzhi Guo","doi":"10.1186/s13062-026-00826-z","DOIUrl":"https://doi.org/10.1186/s13062-026-00826-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCL6B suppresses acute myeloid leukemia progression by transcriptionally repressing GGT5 and modulating MAPK signaling.","authors":"Yuqing Pan, Kun Wu, Xiaobo Ma, Shenju Cheng, Chong Guo, Yixun Li, Yanliang Zhang, Yan Du","doi":"10.1186/s13062-026-00823-2","DOIUrl":"https://doi.org/10.1186/s13062-026-00823-2","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ETV4 promotes colorectal cancer progression through SLC7A11-mediated ferroptosis inhibition.","authors":"Zhouzhou Chao, Jinbao Yin, Fengxia Huang, Jinlian Xu, Yingyan Lv, Jiayao Chen, Aijing Xu, Wei Zhu, Jinxing Wang","doi":"10.1186/s13062-026-00816-1","DOIUrl":"https://doi.org/10.1186/s13062-026-00816-1","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally. Ferroptosis, a regulated form of cell death, has emerged as a promising frontier in CRC treatment. The transcriptional regulator ETV4 (ETS variant transcription factor 4) is implicated in CRC pathogenesis. However, its functional role has not been fully elucidated, and its potential to modulate ferroptosis in CRC is entirely unknown. This study aimed to investigate whether ETV4 modulates ferroptosis in CRC by regulating SLC7A11 and to explore the underlying mechanism involved.</p><p><strong>Methods: </strong>Bioinformatic analysis was conducted to detect ETV4 expression and to identify pathways regulated by ETV4. Real‑time quantitative PCR (RT‑qPCR) and Western blot assays were used to measure gene expression at the mRNA and protein levels. The biological functions of ETV4 were assessed via CCK‑8, colony formation, wound‑healing, apoptosis analysis, transmission electron microscopy (TEM) and Transwell assays. Key ferroptosis markers-reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (JC‑1), and ferrous iron (FerroOrange) were examined to determine whether ETV4 knockdown promotes ferroptosis.</p><p><strong>Results: </strong>ETV4 is highly expressed in CRC tissues and cell lines, and its expression level is positively correlated with advanced TNM stages. Silencing ETV4 suppressed CRC cell proliferation, clonogenicity, and migration. Bioinformatic analysis confirmed that ETV4 may suppress the ferroptosis pathway. Functional assays revealed that ETV4 knockdown enhanced ferroptosis in CRC cells. Mechanistically, ETV4 depletion downregulated SLC7A11, whereas SLC7A11 overexpression reversed the ferroptosis phenotype induced by ETV4 knockdown.</p><p><strong>Conclusion: </strong>ETV4 promotes CRC progression by inhibiting ferroptosis through the upregulation of SLC7A11. Therefore, the ETV4/SLC7A11 axis represents a potential therapeutic target for CRC treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HucMSC-derived exosomes alleviate inflammatory bowel disease via upregulating FXR to suppress macrophage ferroptosis.","authors":"Yuxuan Xia, Ting Sun, Mengjiao Zhou, Bo Wang, Fei Mao","doi":"10.1186/s13062-026-00820-5","DOIUrl":"https://doi.org/10.1186/s13062-026-00820-5","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by excessive inflammation and intestinal damage. Known for its chronic and relapsing nature, IBD currently lacks curative pharmacological therapies. Herein, we investigated the therapeutic potential of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) in IBD and explored the underlying mechanisms. In vivo and in vitro experiments demonstrated that the administration of hucMSC-Ex significantly attenuated inflammatory levels and ameliorated associated disease symptoms in IBD models. Concurrently, hucMSC-Ex treatment effectively modulated bile acid dysregulation in the IBD condition, contributing to the restoration of intestinal metabolic homeostasis. Mechanistically, the protective effects of hucMSC-Ex were mediated through the upregulation of farnesoid X receptor (FXR) expression. FXR, a critical regulator of intestinal homeostasis, plays a pivotal role, particularly in bile acid metabolism. Elevated FXR expression further suppressed ferroptosis in macrophages, as evidenced by reduced lipid peroxidation, diminished oxidative stress, restored iron metabolism homeostasis, and normalized expression of ferroptosis-related markers (GPX4, ACSL4, MBOAT1). Collectively, our findings indicate that hucMSC-Ex alleviates IBD by activating FXR in macrophages, thereby inhibiting lipid peroxidation and reducing ferroptosis, ultimately mitigating inflammation and ameliorating intestinal damage. This offers the potential of a FXR-targeted therapeutic strategy based on exosomes for the treatment of IBD.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147761972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovering non-linear dynamics of miRNAs in Alzheimer's disease-related cognitive impairment: a cross-species approach with explainable machine learning.","authors":"Seong-Hun Lee, Shin Kim, Seung-Bo Lee","doi":"10.1186/s13062-026-00819-y","DOIUrl":"https://doi.org/10.1186/s13062-026-00819-y","url":null,"abstract":"<p><strong>Background: </strong>MicroRNA (miRNA) biomarker studies in Alzheimer's disease (AD) typically assume monotonic relationships between expression levels and disease status, overlooking the non-linear, context-dependent nature of miRNA regulatory networks. This simplification limits mechanistic insight and clinical translation. We aimed to characterise non-linear contribution patterns of miRNAs across the AD continuum using explainable machine learning and to define stage-specific \"operating windows\" where individual miRNAs drive classification.</p><p><strong>Methods: </strong>Candidate miRNAs were prioritised from APPtg/TAUtg mouse hippocampus (accession number GSE110743) using minimum-redundancy-maximum-relevance selection. A three-miRNA panel (miR-155-5p, miR-339-5p, and miR-455-5p) was validated in human serum (GSE120584; AD, MCI, and healthy controls). Linear and non-linear classifiers were compared, and SHAP dependence analysis was used to quantify sample-level contributions across expression ranges.</p><p><strong>Results: </strong>Non-linear models (SVM-RBF and k-NN) consistently outperformed linear classifiers, with discrimination strongest for MCI vs. healthy controls (AUC: 0.844). SHAP analysis revealed that miR-155-5p functions as a stable primary driver across disease stages, whereas miR-339-5p and miR-455-5p act as context-dependent modulators contributing only within restricted expression ranges. Each miRNA exhibited distinct, stage-specific non-linear operating windows with threshold effects and inflection points rather than uniform dose-response patterns.</p><p><strong>Conclusions: </strong>This study reframes circulating miRNAs as dynamic, interaction-governed signals rather than static biomarkers. The operating window framework provides interpretable, threshold-aware guidance for clinical decision-making and supports stage-sensitive early screening strategies.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}