BioFactors最新文献

{"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, Chongyan Liu, Hongxu Zhang, Mingzhao Zhang","doi":"10.1002/biof.70148","DOIUrl":"10.1002/biof.70148","url":null,"abstract":"<p><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>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":"e70148"},"PeriodicalIF":5.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530316/pdf/","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":"OA","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, Jianhai Wu, Qingqi Hong, Hexin Lin, Yongwen Li, Donghan Chen, Haibin Wang, Yifu Chen, Jun You, Yinan Chen","doi":"10.1002/biof.70145","DOIUrl":"https://doi.org/10.1002/biof.70145","url":null,"abstract":"<p><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>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":"e70145"},"PeriodicalIF":5.2,"publicationDate":"2026-09-01","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, Yu Liu, Yuan Peng, Yanli Zeng, Zhibin Luo","doi":"10.1002/biof.70136","DOIUrl":"10.1002/biof.70136","url":null,"abstract":"<p><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>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 5","pages":"e70136"},"PeriodicalIF":5.2,"publicationDate":"2026-09-01","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":"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}

{"title":"miR-200a-3p Targets and Downregulates CDC25B Expression to Inhibit the Progression of Hepatocellular Carcinoma","authors":"Zixiang Huang,&nbsp;Xi Yu","doi":"10.1002/biof.70143","DOIUrl":"10.1002/biof.70143","url":null,"abstract":"<div>\u0000 \u0000 <p>Cancer originates from the uncontrolled proliferation of normal cells. Previous studies have demonstrated that CDC25B, a cell cycle-regulating phosphatase, is overexpressed in various tumors, including hepatocellular carcinoma, and its expression level may serve as a prognostic biomarker. The present study investigated the upstream miRNA regulators of CDC25B and demonstrated that their interactions can inhibit hepatocellular carcinoma progression. Here, stable hepatocellular carcinoma cell lines overexpressing or knocking down CDC25B were established using lentiviral vectors. The effects of CDC25B expression on the invasive phenotype of hepatocellular carcinoma cells were analyzed using plate cloning, scratch assays, and Transwell assays, and a subcutaneous tumor xenograft model in mice was established to evaluate the impact of CDC25B on tumor growth in vivo. Furthermore, dual-luciferase reporter assays were used to validate the targeted regulatory relationship between miR-200a-3p and CDC25B, while miR-200a-3p mimics and inhibitors were employed to elucidate the specific downstream mechanisms. We found that high expression of CDC25B significantly enhanced the epithelial–mesenchymal transition process, thereby accelerating the proliferation, invasion, and migration of hepatocellular carcinoma cells, whereas CDC25B knockdown exerted the opposite effects. In vivo tumorigenicity experiments in nude mice confirmed that overexpression of CDC25B promoted tumor growth. In addition, the dual-luciferase reporter assay confirmed that miR-200a-3p specifically targets and downregulates CDC25B expression, thereby inhibiting hepatocellular carcinoma progression.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 4","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720009","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":"HILPDA Repression Induces Methuosis in Breast and Liver Cancer Cells by Dysregulating Lipid Metabolism","authors":"Jie Wang,&nbsp;Chuanxin Zhai,&nbsp;Chengfei Zhang,&nbsp;Anlian Fan,&nbsp;Sajid Jalal,&nbsp;Ting Zhang,&nbsp;Ting Xu,&nbsp;Chuanzhou Gao,&nbsp;Xinran Chen,&nbsp;Hongming Teng,&nbsp;Yuanyuan Luo,&nbsp;Cong Li,&nbsp;Lin Huang","doi":"10.1002/biof.70142","DOIUrl":"https://doi.org/10.1002/biof.70142","url":null,"abstract":"<div>\u0000 \u0000 <p>Perturbation of macropinocytosis triggers methuosis, a non-apoptotic cell death characterized by cytoplasmic vacuolization. However, the regulatory mechanisms of methuosis remain poorly defined. Lipid metabolism dysregulation is implicated in various cell death pathways, while its role in methuosis has remained elusive. Herein, LXX-8250, an isopropanolamine derivative of β-elemene, induced a vacuolization-associated cell death in breast and liver cancer cell lines. This process was accompanied by massive macropinocytosis, thereby confirming the occurrence of methuosis. Mechanistically, hypoxia-inducible lipid droplet-associated protein (HILPDA), a key regulator that promotes intracellular triacylglycerol (TAG) accumulation, was identified as the direct target of LXX-8250. By suppressing HILPDA, LXX-8250 inhibited diacylglycerol O-acyltransferase 1 (DGAT1) and activated adipose triglyceride lipase (ATGL). Consequently, lipid droplets and cellular TAG levels were reduced, while the subsequent increased diacylglycerol (DAG) stimulated macropinosome formation, leading to methuosis in these cells. In this study, we discover a novel methuosis agonist LXX-8250, and elucidate the critical role of HILPDA repression-dysregulated lipid metabolism in methuosis. Our study highlighted the potential of targeting this pathway as a therapeutic strategy to trigger cancer cell death.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 4","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753738","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":"Differential Modulation of Keratinocyte Proliferation, Differentiation, and Barrier Function by Hemp Oil, Blackcurrant Seed Oil, and Vitamin D3 Under Atopic-Associated Cytokine Stimulation","authors":"Daniel Tortolani,&nbsp;Lucia Scipioni,&nbsp;Alessandro Anselmucci,&nbsp;Francesca Ciaramellano,&nbsp;Meri Di Leonardo,&nbsp;Isa Fusaro,&nbsp;Sergio Oddi,&nbsp;Alessandro Gramenzi","doi":"10.1002/biof.70137","DOIUrl":"10.1002/biof.70137","url":null,"abstract":"<p>Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation, altered differentiation, barrier dysfunction, and oxidative stress. Currently available therapies, including monoclonal antibodies and JAK inhibitors, have improved AD management but do not address all aspects of the disease, supporting the investigation of natural-product strategies as complementary approaches to long-term care. An acute in vitro model of canine atopic-like inflammation was established by exposing canine progenitor epidermal keratinocytes (CPEK) for 24 h to a defined cytokine cocktail (IFN-γ, IL-4, IL-13), followed by 24 h of treatment with hemp oil, blackcurrant seed oil, vitamin D₃, or their combination. Proliferation (Ki-67, cell-cycle), differentiation (KRT5, KRT10, TGM1, involucrin), tight-junction organization (CLDN1, TJP1, ZO-1, TEER), wound closure, nitrosative stress (3-nitrotyrosine), the NRF2/BACH1/HMOX1 axis, and the secretion of STAT1- and NF-κB-dependent inflammatory mediators (CXCL9, CXCL10, IL-8, IL-6) and the STAT6-targeted chemokine CCL17 were assessed. The cytokine cocktail induced a coherent AD-like phenotype: increased Ki-67, downregulated CLDN1, sustained nitrosative stress, NRF2 elevation paralleled by BACH1 induction, and robust secretion of STAT1- and NF-κB-dependent mediators. The four treatments modulated this phenotype according to clearly differential, pathway-specific profiles. Vitamin D₃, alone or combined, emerged as the most effective modulator of proliferation and acted preferentially on the downstream redox arm, inducing HMOX1 and reducing BACH1; both vitamin D₃-containing formulations exerted broad anti-inflammatory activity across the STAT1 and NF-κB axes. Hemp oil acted preferentially on tight-junction integrity (CLDN1 recovery), on the upstream NRF2 arm (NFE2L2 induction), on the STAT1 chemokine arm (CXCL9, CXCL10 reduction), and on wound closure. Blackcurrant seed oil acted preferentially on NF-κB-dependent IL-8 and on early wound-closure dynamics. This differential pharmacological footprint provides a rational basis for further investigation of these formulations as nutraceutical adjuncts in canine AD.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 4","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705225","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}