Biology Direct最新文献

{"title":"Bovine lactoferrin induces apoptosis and modulates the transcriptomic landscape of HeLa cervical cancer cells.","authors":"Yu Zhao, Rui Liu, Mengtian Li, Mingzhuang Feng, Yuting Bao, Guoxin Chen, Haixia Zhang","doi":"10.1186/s13062-026-00859-4","DOIUrl":"10.1186/s13062-026-00859-4","url":null,"abstract":"<p><p>Cervical cancer (CC) remains a leading malignancy among women worldwide. Current management strategies, including surgery, radiotherapy, chemotherapy, targeted therapy, and prevention, often cause significant adverse effects and demonstrate limited efficacy in advanced disease. Consequently, identifying novel therapeutic strategies and drug targets, particularly low-toxicity, high-specificity natural agents-constitutes a critical research priority. Bovine lactoferrin (bLF), a multifunctional iron-binding glycoprotein, demonstrates therapeutic potential, though its precise molecular mechanisms in cervical cancer are incompletely understood. This study therefore examined the biochemical and transcriptomic alterations in bLF-treated cervical cancer cells to elucidate its mode of action. bLF suppressed HeLa cell viability in a dose-dependent manner and concurrently promoted apoptosis while inhibiting proliferation and migration. The bLF-induced apoptosis appears to arise from a synergistic multi-mechanistic interplay, potentially involving increased intracellular ROS levels, downregulated mitochondrial membrane potential, or modulated expression of autophagy-related proteins to activate autophagic pathways. RNA sequencing identified substantial transcriptomic changes in cancer-associated pathways, notably affecting cell cycle progression, protein transport, apoptotic processes, and the negative regulation of apoptosis. These results substantiate the potent anticancer activity of bLF and highlight its promise as a therapeutic candidate derived from a natural product.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and prognostic analysis of genes related to CTNNB1 mutations in hepatocellular carcinoma.","authors":"Ningqi Zhu, Guo Zhang, Xiaotian Shen, Zule Chen, Ying Li, Diyu Chen, Huliang Jia","doi":"10.1186/s13062-026-00873-6","DOIUrl":"10.1186/s13062-026-00873-6","url":null,"abstract":"<p><strong>Background: </strong>Mutations in CTNNB1 are recognized oncogenic drivers of hepatocellular carcinoma (HCC); however, the downstream effector molecules and their prognostic significance remain incompletely defined. In this study, we developed a mutant CTNNB1 gene signature (MCGS) to predict CTNNB1 mutation status and to evaluate the prognostic relevance of the constituent genes.</p><p><strong>Methods: </strong>Hydrodynamic tail vein injection mouse models of HCC were generated by co-expressing Sleeping Beauty transposon/transposase and mutant CTNNB1 with either AKT-c-Myc or AKT-NRAS^G12V, followed by RNA sequencing of tumor tissues. Cross-species differential expression analyses were performed by integrating data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Machine-learning models were trained to identify MCGS. The prognostic value of signature genes was validated using public transcriptomic datasets and immunohistochemistry on an institutional tissue microarray (TMA) cohort.</p><p><strong>Results: </strong>Mutant CTNNB1 markedly accelerated hepatocarcinogenesis in mice, leading to earlier tumor development and reduced survival. Transcriptomic profiling revealed enrichment of the Hippo and MAPK signaling pathways in CTNNB1-mutant HCCs. We established a 15-gene MCGS using a Categorical Boosting algorithm, which accurately predicted CTNNB1 mutation status (AUC = 0.957 in TCGA; 0.893 in ICGC). Among these genes, metallothionein-3 (MT3) emerged as a prognostic marker, with high expression independently associated with poorer overall survival in public datasets. Consistently, elevated MT3 protein expression on the TMA was also independently associated with worse overall and recurrence-free survival in our institutional cohort.</p><p><strong>Conclusion: </strong>We identified a robust mutant CTNNB1 gene signature capable of accurately predicting CTNNB1 mutation status, and uncovered MT3 as a novel, clinically relevant prognostic biomarker in HCC.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TrxR1 inhibition sensitizes hepatocellular carcinoma to Motesanib via an autophagy-ROS-JNK/ER stress axis.","authors":"Shengwei Du, Peisen Zheng, Wen Li, Guorong Chen, Hanbin Chen","doi":"10.1186/s13062-026-00874-5","DOIUrl":"10.1186/s13062-026-00874-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with a dismal prognosis, largely due to the limited effectiveness of current therapeutic interventions. Although Motesanib (MOT) is a clinically studied VEGFR-centered inhibitor, VEGFR-targeted strategies remain limited by innate or acquired resistance. In this study, we explored a novel pharmacological strategy combining MOT with Auranofin (AF) to enhance therapeutic outcomes in HCC. Our data demonstrate that this dual-targeting approach yields robust synergistic anticancer activity across diverse experimental models. Mechanistically, we discovered that TrxR1 inhibition is critical for this sensitization, which is closely associated with autophagy-related reactive oxygen species (ROS) accumulation. Specifically, genetic depletion of Atg5 effectively suppressed ROS accumulation and attenuated cytotoxicity, suggesting that autophagy contributes to the synergistic oxidative damage. This orchestrated stress response subsequently led to sustained endoplasmic reticulum (ER) stress and JNK pathway activation, culminating in DNA damage, impaired proliferation, and reduced cell viability. Taken together, our results identify the combination of MOT and AF as a promising and mechanistically grounded treatment regimen for advanced HCC (Graphical Abstract).</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed cell death-related gene S100A9 promotes macrophage M1 polarization and chondrocyte apoptosis in rheumatoid arthritis.","authors":"Qingyuan Xu, Jinfu Liu, Qiang Ding, Canbin Zhao, Weiwei Wang, Hao Li, Chicheng Niu, Wei Chen, Ping Zeng, Donghui Guan, Ronghua Zhang","doi":"10.1186/s13062-026-00866-5","DOIUrl":"10.1186/s13062-026-00866-5","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is a heterogeneous chronic autoimmune disease. Its high disability rate has a serious impact on individuals and society. Programmed cell death (PCD) patterns play a key role in several diseases. However, the significance of the interplay between PCD and RA remains underexplored.</p><p><strong>Methods: </strong>In total, 18 PCD patterns were analyzed for the model construction. Single-cell RNA-seq transcriptome (scRNA-seq) and bulk RNA-seq data were collected from the GSE200815, GSE1919, GSE77298, GSE206848, GSE89408, GSE12021, GSE55235, and GSE55457 cohorts to validate the model. In vivo and in vitro experiments were performed to determine the role of S100A9 in RA.</p><p><strong>Results: </strong>We developed a programmed cell death-related (PCDR) model for RA using 113 combinations of 12 machine learning algorithms and significant PCD signatures; 2 RA clusters were identified. A significant difference was noted in the macrophage numbers between the two groups. Macrophages were identified as key effector cells that play a central role in RA pathogenesis through cellular communication and the transition of cell states. S100A9 was identified as a key gene in the PCDR model, and its knockdown significantly slowed RA progression by reducing joint synovitis and cartilage damage. M1 macrophage polarization was accompanied by the overexpression of S100A9 in the synovial tissues of RA model mice. Compared with RA mice, AAV-shRNA-mediated S100A9 knockdown mice showed decreased M1 macrophage polarization, attenuated severity of synovitis, and elevated expression of the cartilage phenotype proteins-collagen II and BCL-2. Additionally, S100A9 knockdown inhibited M1 macrophage polarization in vitro. Hence, S100A9 inhibition may be a promising therapeutic strategy for RA treatment.</p><p><strong>Conclusion: </strong>We established a novel PCDR model by comprehensively analyzing diverse cell death patterns. S100A9 inhibition may be a promising therapeutic strategy for RA treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive multi-omics analysis reveals a fatty acid metabolism gene signature for prognostic assessment and immunotherapy in nasopharyngeal carcinoma, and identifies ABCC1 as a potential novel therapeutic target.","authors":"Yang Xu, Liru Zhu, Qingqing Zhang, Xiaojun Chen, Haoyu Lv, Shuhan Ma, Runzhi Wang, Yuanyuan Chang, Yongchu Sun, Kaihua Chen, Ling Li, Xiaodong Zhu","doi":"10.1186/s13062-026-00875-4","DOIUrl":"10.1186/s13062-026-00875-4","url":null,"abstract":"<p><strong>Background: </strong>Nasopharyngeal carcinoma (NPC) is a subtype of head and neck squamous cell carcinoma characterized by high recurrence and metastasis rates and poor prognosis. Although immune checkpoint inhibitors have emerged as a promising treatment strategy for recurrent/metastatic nasopharyngeal carcinoma (R/M NPC), only a few patients have benefitted significantly from them. Lipid metabolism reprogramming plays a crucial role in NPC progression and its interaction with the immune microenvironment. This study aims to establish a prognostic model for NPC based on lipid metabolism-related factors, further explore its association with tumor immunity, and investigate the potential for immunotherapy.</p><p><strong>Methods: </strong>Collect GEO datasets(GSE53819 and GSE102349) for differential expression analysis and least absolute shrinkage and selection operator (LASSO) regression to identify prognostic genes and construct a fatty-acid-metabolism-related prognostic model. Survival analyses and time-dependent receiver operating characteristic (ROC) curves were applied to evaluate the predictive performance of the constructed prognostic markers. Furthermore, associations between the derived risk scores and immunological characteristics were systematically evaluated. Following the identification of ABCC1 as a key gene, its expression was validated through RT-qPCR, immunoblotting, and immunohistochemistry (IHC). Its functional role was further investigated using in vitro functional assays, multiplex immunohistochemistry (mIHC), co-culture experiments with CD8⁺ T cells, and in vivo xenograft tumor models in nude mice.</p><p><strong>Results: </strong>Four genes (ABCC1, CD1D, CYP4B1, and DPEP2) were identified to constr uct a prognostic model associated with fatty acid metabolism. This model revealed significant distinctions in immune infiltration patterns between high-risk and low-risk groups. Specifically, the high-risk group displayed immunosuppressive characteristics, marked by reduced infiltration of CD8⁺T cells. Functional studies demonstrated that ABCC1 promoted NPC cell proliferation, migration, invasion, ROS accumulation, and lipid metabolic reprogramming. Mechanistically, ABCC1 was epigenetically upregulated by the histone acetyltransferase P300 and contributed to CD8⁺ T cell dysfunction and MEK/ERK pathway activation, thereby driving tumor progression.</p><p><strong>Conclusion: </strong>In summary, we established a novel fatty-acid-metabolism-related prognostic model for assessing the prognosis and potential immunotherapy response of NPC patients, as well as for characterizing the immunological features of the tumor microenvironment (TME). Furthermore, ABCC1 emerged as a promising prognostic biomarker associated with immunotherapeutic responsiveness in NPC, warranting further validation.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 microbiome-metabolome analysis implicates Acinetobacter guillouiae in arachidonic acid metabolic remodeling and endometrial cancer cell proliferation.","authors":"Wenjing Ma, Jie Pi, Huanzhi Wan, Haoyu Wang, Wuyue Han, Min Hu, Jingchun Liu","doi":"10.1186/s13062-026-00877-2","DOIUrl":"10.1186/s13062-026-00877-2","url":null,"abstract":"<p><strong>Background: </strong>Lesion-associated microbiota have emerged as potential regulators of tumor biology. However, the ecological organization and metabolic relevance of the local endometrial microbiome in endometrial cancer (EC) remain incompletely defined. This study aimed to characterize microbiome-associated metabolic alterations in EC tissues.</p><p><strong>Methods: </strong>We performed integrated 16S rRNA sequencing and untargeted metabolomic analyses using paired EC and adjacent non-tumor endometrial tissues. Microbial diversity, taxonomic composition, co-occurrence network architecture, and metabolomic pathway alterations were evaluated. Conditioned medium derived from Acinetobacter guillouiae was used to explore its association with arachidonic acid (AA) metabolism and proliferative phenotypes in EC cells, followed by pharmacological pathway interrogation and xenograft validation.</p><p><strong>Results: </strong>Overall microbial diversity was not significantly different between EC and adjacent tissues, whereas EC tissues exhibited a more connected and centralized microbial co-occurrence network. Taxonomic analyses identified enrichment of A. guillouiae in EC tissues based on 16S rRNA taxonomic assignment. Untargeted metabolomics revealed a group-level metabolic shift in EC tissues, with AA metabolism among the most prominently enriched pathways. In EC cells, A. guillouiae-derived conditioned medium increased intracellular AA levels, enhanced cPLA2 phosphorylation, induced AA-metabolizing enzymes, and activated the TLR4/NF-κB/ALOX5 signaling axis. Pharmacological inhibition of cPLA2, ALOX5, TLR4, or NF-κB partially attenuated the metabolic or proliferative effects associated with A. guillouiae conditioned medium. In a xenograft model, intratumoral exposure to A. guillouiae was associated with accelerated tumor growth.</p><p><strong>Conclusions: </strong>These findings suggest that A. guillouiae-associated microbial alterations may contribute to AA metabolic remodeling and proliferative phenotypes in EC. This study provides a microbiome-metabolome framework for understanding lipid metabolic heterogeneity in EC and supports further validation of bacteria-associated AA metabolism as a potential therapeutic target.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of ESRRA and JUNB in oxyphil cells: insights from spatial transcriptomics and single-cell transcriptomics in uremic secondary hyperparathyroidism.","authors":"Zeyu Zhang, Xiangyuan Qiu, Botao Sun, Xinying Li, Fada Xia","doi":"10.1186/s13062-026-00876-3","DOIUrl":"10.1186/s13062-026-00876-3","url":null,"abstract":"<p><p>Oxyphil cells are a primary cellular component of the parathyroid gland. Due to the limitations of techniques for separating oxyphil cells from chief cells, the characteristics and functions of oxyphil cells in uremic secondary hyperparathyroidism (SHPT) remain largely unclear. Therefore, we integrated spatial transcriptomics and single-cell transcriptomics to investigate the characteristics of oxyphil cells and the association between oxyphil cells and calcitriol resistance in SHPT. 6 uremic SHPT samples and 3 normal parathyroid samples were used for single-cell transcriptomics, while the most suitable SHPT sample was used for spatial transcriptomics. By integrating spatial transcriptomics with single-cell transcriptomics data (93073 cells), we identified a subset of 7653 cells with high confidence as oxyphil cells. Both transcriptomic data indicated a higher mitochondrial transcript proportion in oxyphil cells, and further investigation revealed that the transcription factor estrogen related receptor alpha (ESRRA), participated in mitochondrial biogenesis in these cells. Meanwhile, lower VDR expression and calcitriol resistance were observed in oxyphil cells. Further investigation demonstrated that the transcription factor JUNB promoted the transcription of VDR gene by binding to the promoter area of VDR gene, thus ameliorating calcitriol resistance of oxyphil cells in SHPT. These findings offer reliable evidence and new insights into the characteristics of oxyphil cells and their potential role in SHPT, and provide JUNB as a potential target for calcitriol resistance in SHPT.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13555932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silymarin attenuates diabetic nephropathy in rats via modulation of the miRNA-223/NLRP3/caspase-1/GSDMD axis and inflammasome-related pyroptotic signaling.","authors":"Merna G Aboismaiel, Mohamed N Amin, Laila A Eissa","doi":"10.1186/s13062-026-00857-6","DOIUrl":"10.1186/s13062-026-00857-6","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a progressive microvascular complication of diabetes and a leading cause of end-stage renal disease, with limited disease-modifying therapeutic options. DN is characterized by progressive renal dysfunction, oxidative stress, inflammation, fibrosis, and activation of inflammasome-related pathways. Silymarin, a natural compound with antioxidant and anti-inflammatory properties, has demonstrated renoprotective potential; however, its association with miRNA-223/NLRP3/caspase-1/GSDMD signaling in DN remains incompletely defined. Therefore, the present study investigated the potential renoprotective effects of silymarin in a high-fat diet/streptozotocin (HFD/STZ)-induced rat model of DN, with particular focus on miRNA-223 expression and inflammasome-associated pyroptotic signaling. Diabetic rats received oral silymarin (100 mg/kg/day) either for 12 weeks as an early intervention or 4 weeks as a delayed treatment. Renal function indices, blood glucose, HbA1c, serum insulin, HOMA-IR, LDH, lipid profile, body weight, kidney weight/body weight index, oxidative stress markers, and histopathological changes were evaluated. Renal expression of miRNA-223, NOD-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, gasdermin D (GSDMD), nuclear factor-kappa B (NF-κB) (p65), hypoxia-inducible factor-1 alpha (HIF-1α), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and fibronectin was assessed using RT-qPCR, ELISA, and immunohistochemistry. Silymarin significantly improved renal function, glycemic control, insulin resistance, lipid profile, oxidative stress, inflammatory mediators, HIF-1α expression, LDH activity, histopathological injury, and fibrosis relative to untreated DN rats. Moreover, silymarin was associated with increased renal miRNA-223 expression and reduced expression of NLRP3, caspase-1, and GSDMD. These effects were more pronounced in the early intervention group compared with delayed treatment. In conclusion, silymarin attenuated experimental DN via modulation of the miRNA-223/NLRP3/caspase-1/GSDMD axis and suppression of pyroptosis-associated signaling, alongside improvement of oxidative stress, inflammation, hypoxia, fibrosis, and metabolic disturbances. Further mechanistic studies are warranted to clarify the causal relationship between miRNA-223 modulation and the observed renoprotective effects of silymarin.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13295846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tenascin C promotes the formation of abdominal aortic aneurysm by regulating the homeostasis of vascular smooth muscle cells.","authors":"Xiaoyong Xiao, Jie Xiong, Yixuan Bao, Chixiong Huang, Guona Chen, HongYun Lu, CongMing Yang, Mengsha Li, Weiling Lu, Haoyu Song, Beiyou Lin, Yanxian Lai, Hongbin Liang, Lintao Zhong","doi":"10.1186/s13062-026-00878-1","DOIUrl":"10.1186/s13062-026-00878-1","url":null,"abstract":"<p><strong>Background: </strong>Abdominal aortic aneurysm (AAA) is the most common type of arterial dilation disease. Once ruptured and bleeding, AAA can be life-threatening, with a mortality rate as high as 90%. Vascular smooth muscle cells(VSMCs) dyshomeostasis is the main pathological factor for AAA formation, but the specific regulatory process remains unclear.</p><p><strong>Methods: </strong>Firstly, we employed single-cell RNA sequencing (scRNA-seq) to reveal the heterogeneity and intercellular communication network of VSMCs in the aorta of AAA patients. We further integrated the data from the public database to clarify differences of the target signal in AAA, and also collected clinical data to analyze both differences and predictive performance for AAA. Subsequently, we generated VSMCs-specific knockout mice in the PPE-induced AAA mouse model to observe formation of AAA and VSMCs dyshomeostasis. Finally, we combined methods such as immunoprecipitation, bioinformatics, western blotting, qPCR, transwell co-culture and luciferase reporter assays to clarify the specific molecular mechanisms underlying VSMCs dyshomeostasis.</p><p><strong>Results: </strong>Through multi-level analysis and experiments, we confirmed that the Tenascin C (TNC) communication signal was significantly highly expressed in the arterial tissue and plasma of AAA, and elevated TNC levels in plasma could predict the occurrence of human AAA. In mouse models, we found that VSMCs-specific TNC knockout could inhibit PPE-induced AAA formation and VSMCs dyshomeostasis. Mechanistically, we revealed that TNC promoted nuclear translocation of NF-κB p50 and p65 through TLR4, thereby causing VSMCs dyshomeostasis, while the endoplasmic reticulum stress factor CHOP could induce TNC production in VSMCs.</p><p><strong>Conclusion: </strong>Our research demonstrates the existence of a TNC-centered signaling axis mediating VSMCs dyshomeostasis in the formation of AAA.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α/NREP axis promotes hypertrophic scar fibroblast proliferation and collagen deposition via activation of the TGF-β1/Smad pathway.","authors":"Baiye Chen, Chaofan Lin, Xueming Wang, Weiwen Zhu, Jiaqi Zhang, Liu Chen","doi":"10.1186/s13062-026-00855-8","DOIUrl":"10.1186/s13062-026-00855-8","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic scar (HS) is a fibroproliferative skin disorder characterized by excessive fibroblast proliferation and collagen overproduction during aberrant wound healing. Although hypoxia is a well-recognized driver of HS formation, the molecular mechanisms linking hypoxic signaling to fibroblast activation remain incompletely understood.</p><p><strong>Methods: </strong>In this study, the expression of hypoxia-inducible factor 1α (HIF-1α), neuronal regeneration-related protein (NREP), and phosphorylated small mother against decapentaplegic family member 2/3 (p-Smad2/3) was examined in HS and matched normal tissues from patients. Hypertrophic scar fibroblasts (HSFBs) were cultured under hypoxic or normoxic conditions, followed by genetic manipulation of HIF-1α or NREP to assess their effects on fibroblast proliferation and collagen synthesis. The direct transcriptional regulation of NREP by HIF-1α was confirmed using dual-luciferase reporter and ChIP assays.</p><p><strong>Results: </strong>Compared with normal tissues, HS tissues exhibited markedly elevated expression of HIF-1α, NREP, and phosphorylated Smad2/3. Hypoxia significantly increased HIF-1α and NREP levels in HSFBs, promoting fibroblast proliferation and collagen deposition, whereas knockdown of either HIF-1α or NREP abrogated these effects. Mechanistically, HIF-1α directly bound to the NREP promoter to enhance its transcription, and NREP overexpression partially rescued the suppressive effects of HIF-1α knockdown. Furthermore, HIF-1α-induced NREP upregulation activated the TGF-β1/Smad signaling cascade, while inhibition of this cascade counteracted the effect of NREP overexpression on the changes caused by HIF-1α silencing.</p><p><strong>Conclusion: </strong>Our findings identify a novel HIF-1α/NREP/TGF-β1-Smad axis that drives fibroblast hyperproliferation and excessive collagen accumulation in HS. Targeting this signaling pathway may offer a promising therapeutic strategy for preventing or treating HS formation.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}