BioFactors最新文献

{"title":"Betanin Promotes Wound Closure and Drives a Context-Specific Transcriptional Repair Program in HaCaT Keratinocytes: A Multi-Evidence AI-Guided Prioritization Study","authors":"Sun Young Park,&nbsp;Youjin Kim","doi":"10.1002/biof.70151","DOIUrl":"10.1002/biof.70151","url":null,"abstract":"<p>Keratinocytes coordinate re-epithelialization, barrier restoration, inflammatory control, and matrix remodeling during cutaneous repair. Although betanin has reported cytoprotective and antioxidant properties, its wound-relevant transcriptional program in keratinocytes remains incompletely defined. This study therefore asked whether betanin engages barrier, inflammatory, and remodeling-related keratinocyte programs under inflammatory conditions, and whether existing wound-healing databases can account for the resulting transcriptional pattern. Scratch closure was quantified by ImageJ measurement and by an independent rule-based automated image-analysis pipeline with first-order kinetic modeling; transcriptional responses in IFN-γ/TNF-α-stimulated HaCaT cells were interpreted through database-weighted evidence scoring and machine learning-based stress testing. Betanin (20 μg/mL) significantly reduced residual wound area at 24 h (<i>p</i> = 0.020) and 48 h (<i>p</i> = 0.035) by ImageJ quantification, and automated image analysis with kinetic modeling yielded an approximately 1.5-fold higher first-order closure rate constant relative to the vehicle-treated wounded control. Betanin partially restored <i>FLG</i>, reduced <i>KRT14</i>, and selectively attenuated inflammatory mediators including <i>IL1B</i>, <i>ICAM1</i>, <i>CCL22</i>, and <i>CXCL8</i>. Among remodeling-associated genes, <i>TGFB1</i>, <i>COL1A1</i>, and <i>VEGFA</i> were suppressed while <i>COL3A1</i> was partially restored. <i>NFE2L2</i> and <i>HMOX1</i> were only modestly affected, indicating a dominant anti-inflammatory and barrier-modulating response rather than canonical antioxidant axis activation. Database-weighted evidence scoring stably prioritized <i>FLG</i>, <i>COL3A1</i>, <i>COL1A1</i>, and <i>ICAM1</i>, corroborated by betanin-specific experimental responses. Three architecturally distinct machine learning models showed no evidence that database-derived wound-healing features predict betanin-induced transcriptional responses, indicating that the selected prior-knowledge annotations were insufficient to account for the observed pattern in this 15-gene, single-context dataset.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.70151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Omics-Enabled Precision Strategies for Overcoming CAR-T Therapy Limitations in Gastrointestinal Malignancies","authors":"Ke Su,&nbsp;Zunyuan Tan,&nbsp;Han Li,&nbsp;Kai You,&nbsp;Susu Xiao,&nbsp;Haiqing Chen,&nbsp;Danyang Li,&nbsp;Xin Liu,&nbsp;Xinrui Du,&nbsp;Jiaxin Hu,&nbsp;Kun He,&nbsp;Yantian Xu,&nbsp;Jian Chen,&nbsp;Yunwei Han","doi":"10.1002/biof.70150","DOIUrl":"10.1002/biof.70150","url":null,"abstract":"<div>\u0000 \u0000 <p>Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune-Like Malignant Epithelial Programs Shape Tumor–Immune Interactions and Inform Prognostic Stratification in Lung Adenocarcinoma","authors":"Wei Zhang,&nbsp;Hongmei Sheng,&nbsp;Yazheng Zhang,&nbsp;Qihong Yu,&nbsp;Haiying Peng","doi":"10.1002/biof.70149","DOIUrl":"10.1002/biof.70149","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung adenocarcinoma (LUAD) is characterized by marked cellular heterogeneity, yet how malignant epithelial states contribute to immune regulation and clinical outcomes remains incompletely defined. We integrated single-cell RNA-sequencing data to map the cellular landscape of LUAD and identify malignant epithelial cells based on inferred copy-number alterations. Epithelial states were further examined through trajectory inference, transcription factor analysis, and cell–cell communication profiling. Single-cell-derived genes were subsequently integrated with TCGA and independent GEO cohorts to construct and validate a machine learning-based prognostic signature. Malignant epithelial cells displayed distinct functional programs, including an immune-like state associated with genomic instability, immune-related transcriptional activity, tumor–immune communication, and patient outcomes. The resulting immune-like malignant epithelial cell signature (IMEC-Sig) consistently stratified survival across multiple cohorts. Low IMEC-Sig scores were accompanied by greater immune infiltration, higher immune checkpoint expression, and increased immunophenoscore, whereas high scores were linked to a comparatively immunosuppressive phenotype. Pan-cancer analyses further identified KRT8 as a gene associated with unfavorable prognosis, and functional experiments showed that KRT8 silencing suppressed proliferation, migration, invasion, and colony formation in LUAD cells. Together, these findings connect malignant epithelial heterogeneity with the immune context and clinical outcomes, support IMEC-Sig as a biologically informed prognostic tool, and nominate KRT8 as a potential therapeutic target in LUAD.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Single-Cell and Spatial Transcriptomics Reveal SERPINE1 as a Key Link Between Macro_SPP1 Macrophages and Stromal Remodeling in Gastric Cancer","authors":"Huangdao Yu,&nbsp;Jianhai Wu,&nbsp;Qingqi Hong,&nbsp;Hexin Lin,&nbsp;Yongwen Li,&nbsp;Donghan Chen,&nbsp;Haibin Wang,&nbsp;Yifu Chen,&nbsp;Jun You,&nbsp;Yinan Chen","doi":"10.1002/biof.70145","DOIUrl":"10.1002/biof.70145","url":null,"abstract":"<div>\u0000 \u0000 <p>Macrophage heterogeneity is increasingly recognized as an important feature of the gastric cancer tumor microenvironment, yet the macrophage states linked to poor outcome and the molecules connecting them to stromal remodeling remain incompletely defined. Here, we integrated single-cell RNA sequencing data from GSE183904, spatial transcriptomic data from GSE251950, and TCGA-STAD bulk transcriptomic data to characterize macrophage diversity and identify clinically relevant macrophage-associated genes. Cell–cell communication analysis revealed intensified intercellular signaling in tumors, with prominent changes in MIF, COLLAGEN, FN1, LAMININ, and SPP1 pathways. Five macrophage subclusters were resolved. Among them, macro_SPP1 and macro_IL1B signatures were associated with shorter overall survival, whereas macro_C3_CX3CR1 was linked to a more favorable outcome. By integrating macro_SPP1 markers with tumor-associated differentially expressed genes and applying Cox regression together with multiple machine learning approaches, SERPINE1 emerged as the most consistent prognostic candidate. High SERPINE1 expression was associated with poor survival and with stromal, myeloid, and vascular features. Spatial analysis further localized SERPINE1-high regions to microenvironments enriched for fibroblast- and endothelial-related components and for TGF-β, hypoxia, inflammatory, and extracellular matrix remodeling programs. Virtual perturbation suggested that SERPINE1 may influence myeloid and matrix-related transcriptional networks. Functionally, SERPINE1 knockdown reduced proliferation, colony formation, migration, and invasion in gastric cancer cells. Together, these findings identify SERPINE1 as a macro_SPP1-associated molecule with prognostic and functional relevance and suggest a potential link between macrophage-associated programs, stromal remodeling, and malignant behavior in gastric cancer.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 Biomarker Signatures for Precision Diagnosis and Prognosis in Primary Liver Cancer: A Literature Review","authors":"Ke Xu,&nbsp;Yu Liu,&nbsp;Yuan Peng,&nbsp;Yanli Zeng,&nbsp;Zhibin Luo","doi":"10.1002/biof.70136","DOIUrl":"10.1002/biof.70136","url":null,"abstract":"<div>\u0000 \u0000 <p>Primary liver cancer (PLC) is a biologically heterogeneous group of malignancies dominated by hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and a smaller subset of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and its clinical burden remains high because current diagnostic and prognostic tools do not adequately capture molecular diversity. Conventional imaging, serum markers, and histopathological assessment remain insufficient for precise early diagnosis, subtype-resolved classification, and outcome stratification, while tissue and liquid biopsy approaches have expanded the range of analytes available for clinical assessment. Recent studies have identified candidate biomarker signatures across genomic, epigenomic, transcriptomic, proteomic, metabolomic, and circulating layers, suggesting that integrated multi-omics profiling may better represent tumor lineage, clonal evolution, immune context, and therapeutic vulnerability than isolated molecular readouts. However, these layers are not equally mature for clinical use: genomic testing is closest to routine therapeutic application in iCCA, plasma methylation assays are advancing for HCC surveillance augmentation, and many proteomic or metabolomic panels remain validation-stage tools. Their clinical value remains constrained by sampling bias, biospecimen-dependent signal loss, assay standardization, cost, and the need for prospective validation across clinically diverse populations. This narrative review critically synthesizes current evidence on multi-omics biomarker signatures for precision diagnosis and prognosis in primary liver cancer and argues that clinically useful signatures should be question-specific, stage-aware, and specimen-aware rather than universal multi-analyte panels.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic Profiling Reveals NF-κB-Associated Immune Regulatory Signatures Underlying the Regenerative Effects of Hypoxia-Preconditioned Tendon Stem Cell-Derived Extracellular Vesicles","authors":"Chenfeng He,&nbsp;Chongyan Liu,&nbsp;Hongxu Zhang,&nbsp;Mingzhao Zhang","doi":"10.1002/biof.70148","DOIUrl":"10.1002/biof.70148","url":null,"abstract":"<div>\u0000 \u0000 <p>Remodeling of the immune microenvironment is a critical determinant of tissue regeneration, yet the molecular programs associated with the enhanced therapeutic activity of hypoxia-preconditioned extracellular vesicles remain incompletely defined. In this study, we investigated the regenerative and immunomodulatory effects of hypoxia-preconditioned tendon stem cell-derived extracellular vesicles (Hypo-EVs) and employed transcriptomic profiling to identify molecular signatures associated with their biological activity. The therapeutic effects of Hypo-EVs were evaluated using a rat patellar tendon defect model and lipopolysaccharide-stimulated RAW 264.7 macrophages. Histological analysis, immunostaining, biomechanical testing, and reverse transcription-quantitative polymerase chain reaction were performed to assess tendon healing and macrophage polarization, while RNA sequencing was conducted in macrophages treated with Hypo-EVs or normoxia-derived EVs, followed by Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopaedia of Genes and Genomes pathway analyses. Hypo-EVs significantly alleviated local inflammatory responses, improved collagen organization and biomechanical properties of repaired tendons, and promoted macrophage polarization toward a reparative M2 phenotype both in vivo and in vitro. Consistent with these biological effects, transcriptomic profiling revealed extensive remodeling of inflammation-related gene expression programs, including significant suppression of NF-κB, TNF, IL-17, and cytokine–cytokine receptor interaction pathways. Integrative bioinformatic analyses identified an NF-κB-associated immune-regulatory signature that distinguished Hypo-EV-treated macrophages from those receiving normoxic EVs. Mechanistically, Hypo-EVs attenuated NF-κB activation, as evidenced by reduced phosphorylation of p65 and IκBα, whereas TNF-α-mediated NF-κB activation partially diminished their macrophage-repolarizing effects. Collectively, these findings demonstrate that hypoxic preconditioning enhances the immunomodulatory and regenerative functions of tendon stem cell-derived EVs. Transcriptomic analyses identified an NF-κB-associated immune-regulatory signature linked to the biological activity of Hypo-EVs, providing a molecular framework for understanding EV-mediated immune modulation and supporting the development of transcriptome-guided molecular signatures for regenerative therapies targeting tendon immune homeostasis.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicohort Construction, Immune Landscape Analysis, and PCOLCE2 Functional Validation of an Inflammation-Related Prognostic Model in Colorectal Cancer","authors":"Minjun Dong,&nbsp;Wentao Xu,&nbsp;Jian Zhang,&nbsp;Guiqing Jia","doi":"10.1002/biof.70141","DOIUrl":"https://doi.org/10.1002/biof.70141","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer (CRC) prognosis remains challenging due to tumor heterogeneity and immune evasion driven by aberrant inflammatory signaling, and robust multicohort validated prognostic tools with clear therapeutic implications are still lacking. To address this gap, we integrated five independent CRC cohorts (TCGA, GSE17536, GSE17537, GSE29621, and GSE38832; <i>n</i> = 931) and applied single-sample gene set enrichment analysis (ssGSEA) across 15 inflammation-related signaling pathways to construct a prognostic risk score model via multicohort Cox regression and LASSO-Cox regression. The immune landscape was systematically characterized using immune infiltration algorithms, Cancer Immunity Cycle scoring, CellChat analysis, and single-cell RNA sequencing (scRNA-seq) data (GSE166555). The functional role of the candidate gene PCOLCE2 was further validated through in vitro migration and adhesion assays, and confirmed in a syngeneic C57BL/6 mouse subcutaneous tumor model in which MC38-shPCOLCE2 cells were inoculated and treated with anti-PD-1 antibody (200 μg per mouse, every 3 days) alone or in combination to evaluate the synergistic antitumor effect. The resulting 12-gene inflammation-related risk model achieved robust survival stratification across all five independent cohorts, with AUC values of 0.70–0.85 and C-indices consistently outperforming existing prognostic models, demonstrating strong generalizability as a clinical prognostic tool. High-risk patients exhibited significantly worse overall survival (<i>p</i> &lt; 0.001), an immunosuppressive tumor microenvironment, and elevated pro-stromal remodeling signaling, patterns that were corroborated by single-cell resolution analysis. Mechanistically, PCOLCE2 knockdown suppressed CRC cell migration and enhanced matrix adhesion in vitro. Critically, in vivo combination of PCOLCE2 knockdown with PD-1 blockade produced a synergistic antitumor effect superior to either monotherapy (<i>p</i> &lt; 0.01), highlighting PCOLCE2 as a promising therapeutic target to enhance immunotherapy response. Together, these findings present a clinically actionable, multicohort validated inflammation-related prognostic model for CRC risk stratification, and position PCOLCE2 as a driver of invasion and immune evasion whose combination with PD-1 blockade offers a rational therapeutic strategy to improve immunotherapy efficacy in high-risk CRC patients.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AlCl3 Aerosol Exposure Is Associated With Pulmonary Lactate Accumulation, Neutrophil Dysfunction, and Fibrosis-Like Remodeling","authors":"Jiayu Qin,&nbsp;Fushi Dong,&nbsp;Zhengjie Ye,&nbsp;Xiangxin Yao,&nbsp;Xintong Wang,&nbsp;Tiquan Xiao,&nbsp;Jing Yang,&nbsp;Yan Zheng,&nbsp;Yonggang Cao,&nbsp;Chunli Che","doi":"10.1002/biof.70146","DOIUrl":"10.1002/biof.70146","url":null,"abstract":"&lt;p&gt;Aluminum-associated interstitial lung disease is an exposure-related fibrotic lung disorder, but the metabolic and innate immune mechanisms underlying persistent pulmonary remodeling after aluminum exposure remain incompletely understood. We investigated whether lactate-associated neutrophil dysfunction contributes to lung injury and fibrosis-like remodeling following AlCl&lt;sub&gt;3&lt;/sub&gt; aerosol exposure. Rats were subjected to repeated AlCl&lt;sub&gt;3&lt;/sub&gt; aerosol exposure with or without pharmacological inhibition of lactate transport using the monocarboxylate transporter 1 inhibitor AZD3965. Pulmonary injury, lactate accumulation, inflammatory responses, oxidative stress, DNA damage response signaling, and fibrosis-like remodeling were assessed. Bone marrow-derived rat neutrophils were treated with sodium L-lactate in the presence or absence of AZD3965 to evaluate chemotaxis, oxidative burst, mitochondrial membrane potential, calcium signaling, intracellular lactate accumulation, and neutrophil extracellular trap (NET)-associated responses. In addition, a supportive human cohort comprising patients with aluminum exposure-related interstitial lung disease (Al-ILD), patients with nonaluminum interstitial lung disease (non-Al-ILD), and healthy controls was analyzed using quantitative chest computed tomography (CT), pulmonary function testing, and peripheral blood transcriptomics. Repeated AlCl&lt;sub&gt;3&lt;/sub&gt; aerosol exposure was associated with pulmonary aluminum deposition, lactate accumulation, inflammatory injury, oxidative stress, DNA damage response signaling, neutrophil abnormalities, and collagen-rich fibrosis-like remodeling in rats. In vitro, high-lactate-associated metabolic stress impaired neutrophil chemotaxis, oxidative burst, mitochondrial membrane potential, calcium signaling, and NET-associated responses. AZD3965 reduced intracellular and pulmonary lactate accumulation and partially ameliorated neutrophil dysfunction, inflammatory injury, oxidative stress, and fibrosis-like remodeling in experimental models. In the supportive human cohort, patients with Al-ILD showed greater quantitative CT-defined parenchymal abnormality burden and lower forced vital capacity and diffusing capacity for carbon monoxide than patients with non-Al-ILD. Peripheral blood transcriptomic analysis revealed enrichment of innate immune, cytokine signaling, extracellular matrix organization, and NET-related pathways in Al-ILD. Collectively, these findings indicate that AlCl&lt;sub&gt;3&lt;/sub&gt; aerosol exposure is associated with pulmonary lactate accumulation, neutrophil dysfunction, and fibrosis-like remodeling. Pharmacological modulation of lactate transport provides supportive evidence for the involvement of lactate-associated metabolic regulation in this process, although further studies are required to define the specific molecular targets involved. The integration of experimental and supportive human findings suggests that the lactate–neutrophil dysfunction axis may ","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 4","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13500741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HCC-Derived Alpha-Fetoprotein Impairs Bone Regeneration by Impairing Autophagic Flux and Promoting Runx2 Degradation in Osteoblasts","authors":"Hyung-Mun Yun,&nbsp;Kyung-Ran Park","doi":"10.1002/biof.70147","DOIUrl":"10.1002/biof.70147","url":null,"abstract":"<div>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is frequently complicated by bone metastasis, leading to severe skeletal-related events. While alpha-fetoprotein (AFP) is the gold-standard biomarker for HCC diagnosis, its functional role as a systemic or paracrine mediator in the bone metastatic microenvironment remains largely unexplored. In the present study, we investigated whether HCC-secreted AFP impairs bone formation by disrupting autophagic flux, the glycogen synthase kinase 3β (GSK3β)/β-catenin signaling pathway, and Runt-related transcription factor 2 (Runx2) stability in osteoblasts. Our results showed that AFP dose-dependently inhibited osteoblast differentiation and mineralization. Mechanistically, AFP impaired autophagic flux, resulting in reduced phosphorylated GSK3β (p-GSK3β) and β-catenin levels, which were accompanied by decreased Runx2 protein expression. Pharmacological activation of autophagy with rapamycin effectively reversed these AFP-induced changes, restoring GSK3β/β-catenin signaling and Runx2 expression. Furthermore, using an ex vivo mouse calvarial defect model, we found that HepG2-derived AFP markedly impaired new bone regeneration and reduced the numbers of osteoblasts and osteocytes. Importantly, these effects were significantly attenuated by AFP silencing in HepG2 cells. Collectively, our findings identify HCC-derived AFP as a potential mediator of bone impairment rather than solely a diagnostic biomarker. Targeting AFP-mediated impairment of autophagic flux may represent a promising therapeutic strategy for mitigating skeletal complications and restoring bone homeostasis in patients with bone-metastatic HCC.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 4","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Identifies SCO2 as a Metabolic Reprogramming Gene Promoting Lipid Accumulation in MAFLD","authors":"Along Li,&nbsp;Ronglin Xu,&nbsp;Liangliang Zhang,&nbsp;Xinjian Xu,&nbsp;Longfei Dai,&nbsp;Zhen Zhang","doi":"10.1002/biof.70144","DOIUrl":"https://doi.org/10.1002/biof.70144","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;p&gt;Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease characterized by metabolic dysregulation, inflammation, and fibrosis. Metabolic reprogramming is increasingly recognized as a key molecular driver of MAFLD progression; however, systematic identification of the genes involved remains limited. This study aimed to identify key metabolism reprogramming genes (KMRGs) associated with MAFLD using multi-cohort bioinformatics analyses and machine learning, and to validate their expression patterns and potential roles experimentally. Six MAFLD-related liver transcriptomic datasets were downloaded from the GEO database. GSE135251 and GSE126848 were merged to form the training cohort, whereas the remaining four datasets served as external validation cohorts. Differentially expressed genes (DEGs) were identified and intersected with metabolism reprogramming genes (MRGs) to obtain KMRGs. Functional enrichment analysis, disease association analysis, GeneMANIA network analysis, external validation, immune infiltration analysis, inflammation- and lipid metabolism/fibrosis-related analyses, and consensus clustering were subsequently performed. Machine learning models were then constructed, and SHapley Additive exPlanations (SHAP) analysis was used to prioritize key genes. Finally, the selected gene was experimentally validated using clinical liver tissue samples, free fatty acid (FFA)-induced steatosis models in AML12 and HepG2 cells, qRT-PCR, Western blotting, and Oil Red O staining. Ten KMRGs closely associated with MAFLD were identified. Functional enrichment analysis showed that these genes were mainly involved in PPAR signaling, epigenetic regulation, and FOXO-mediated oxidative stress and metabolic transcriptional processes. A transcriptome-based classification model for MAFLD was constructed using the Naive Bayes machine learning algorithm, and SHAP analysis identified SCO2 as a feature with relatively high importance in model prediction. External validation demonstrated that KMRGs exhibited abnormal expression patterns, diagnostic potential, and correlations with NAFLD activity score (NAS) across different cohorts. Further analyses showed that KMRGs were closely associated with immune microenvironment remodeling, inflammatory responses, lipid metabolic dysregulation, and fibrosis in MAFLD, and could define molecular subtypes with distinct pathological features. Experimental validation showed that SCO2 was highly expressed in clinical MAFLD samples and in FFA-induced in vitro steatosis models. Functional assays further indicated that SCO2 modulated FFA-induced lipid accumulation in vitro. KMRGs are closely associated with the presence and pathological activity of MAFLD. Among them, SCO2 showed high feature importance in machine learning analyses and was associated with FFA-induced lipid accumulation in vitro, suggesting that it is a candidate molecule for further mechanistic investigat","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 4","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}