Frontiers in bioscience (Landmark edition)最新文献

{"title":"TGM2 Activates the ERK Signaling Pathway to Disrupt Intestinal Barrier Function and Aggravate Colitis.","authors":"Hong Dai, Longfei Dai, Yufeng Xu, Xiaojing Liu","doi":"10.31083/FBL55382","DOIUrl":"https://doi.org/10.31083/FBL55382","url":null,"abstract":"<p><strong>Background: </strong>PANoptosis-related transcriptional programs may contribute to pediatric ulcerative colitis (UC), but the genes most consistently associated with disease activity and epithelial injury remain uncertain.</p><p><strong>Methods: </strong>Public transcriptomic cohorts were integrated with machine-learning feature selection, treatment-response analyses, immune cell deconvolution, molecular clustering, and two-sample Mendelian randomization (MR). Transglutaminase 2 (TGM2) expression was examined in colonic specimens from six pediatric patients with UC and six controls. TGM2 knockdown was evaluated in lipopolysaccharide-stimulated HT29 cells using inflammatory gene analysis, tight junction protein measurements, RNA sequencing, and MAPK signaling assays.</p><p><strong>Results: </strong>A total of 17 differentially expressed PANoptosis-related genes were identified, and <i>CCL2</i>, <i>JAK3</i>, and <i>TGM2</i> were prioritized as candidate genes. In the external GSE126124 cohort, <i>TGM2</i> yielded an area under the curve of 0.918 in colonic tissue and 0.744 in peripheral blood. <i>TGM2</i> expression was associated with disease activity, inflammatory cell estimates, barrier-related gene expression, and treatment response. Six single-nucleotide polymorphisms (SNPs) were included in the MR analysis. The inverse-variance weighted estimate was significant (odds ratio 1.486, 95% confidence interval 1.055-2.092; <i>p</i> = 0.023), whereas the other four methods were not significant. In LPS-stimulated HT29 cells, TGM2 knockdown was accompanied by lower <i>TNF-α</i>, <i>IL-1β</i>, and <i>IL-6</i> expression, increased ZO-1, Occludin, and Claudin-3 abundance, and reduced ERK phosphorylation; substantial changes in JNK or p38 phosphorylation were not detected.</p><p><strong>Conclusion: </strong>TGM2 was identified as a candidate through PANoptosis-related bioinformatic screening. TGM2 expression was associated with pediatric UC activity and treatment response, whereas TGM2 knockdown was associated with reduced inflammatory gene expression, increased tight junction protein abundance, and lower ERK phosphorylation in LPS-stimulated HT29 cells. Functional involvement of TGM2 in PANoptosis and its mechanistic position within ERK signaling require further validation.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"55382"},"PeriodicalIF":3.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMEM61 Promotes Malignant Behaviors and Maintains Genomic Stability in Ovarian Cancer Cells.","authors":"Zhizheng Dai, Ruilian Tong, Kai-Fu Tang","doi":"10.31083/FBL54612","DOIUrl":"https://doi.org/10.31083/FBL54612","url":null,"abstract":"<p><strong>Background: </strong>Transmembrane protein 61 (TMEM61) has previously been reported in several malignancies. However, its function in ovarian cancer remains unclear. Here, we aimed to investigate the role and underlying mechanisms of TMEM61 in ovarian cancer cells.</p><p><strong>Methods: </strong>Differentially expressed genes were identified by analyzing transcriptomic data of 426 ovarian cancer tissues from The Cancer Genome Atlas database and 88 normal ovarian tissues from the Genotype-Tissue Expression database using the web-based analytical tool GEPIA2. The effects of TMEM61 knockdown on ovarian cancer cell invasion, migration, and proliferation were evaluated using Transwell, wound healing, and Cell Counting Kit-8 assays. The effect of TMEM61 knockdown on DNA damage and cytosolic DNA accumulation was assessed using immunofluorescence and comet assays. TMEM61 and programmed death-ligand 1 (PD-L1) expression levels were assessed using immunoblotting and reverse transcription-quantitative polymerase chain reaction.</p><p><strong>Results: </strong>TMEM61 exhibited very low expression in normal ovarian tissues, but its expression was significantly upregulated in ovarian cancer tissues. TMEM61 knockdown significantly inhibited the proliferation, migration, and invasion of ovarian cancer cells; induced DNA damage and cytoplasmic DNA accumulation; and upregulated PD-L1 expression in ovarian cancer cells.</p><p><strong>Conclusions: </strong>TMEM61 promotes malignant behavior and maintains genomic stability in ovarian cancer cells. TMEM61 may serve as a potential biomarker and molecular target for ovarian cancer.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"54612"},"PeriodicalIF":3.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excessive Stretch of Airway Smooth Muscle (but Not Epithelial) Cells Activates Paracrine TGF-β1 to Induce Smad2-Mediated G1 Arrest in Airway Epithelial Cells.","authors":"Mingzhi Luo, Jing Zhang, Kai Ni, Xuanyu Shi, Hang Li, Lei Liu, Yan Pan, Jingjing Li, Linhong Deng","doi":"10.31083/FBL55462","DOIUrl":"https://doi.org/10.31083/FBL55462","url":null,"abstract":"<p><strong>Background: </strong>Although mechanical ventilation (MV)-associated excessive stretch directly damages airway epithelial cells (AECs) and contributes to ventilator-induced lung injury (VILI), the contribution of paracrine factors from airway cells, particularly airway smooth muscle cells (ASMCs) and AECs, remains poorly understood. As stretch-sensitive cells, ASMCs and AECs may respond to excessive stretch by secreting paracrine factors such as transforming growth factor β1 (TGF-β1), thereby disrupting airway epithelial integrity. This study compared the sensitivity of cultured ASMCs and AECs to MV-associated excessive stretch and their ability to induce paracrine factors, particularly TGF-β1, that inhibit AEC proliferation <i>in vitro</i>.</p><p><strong>Methods: </strong>Human ASMCs and AECs (16HBE14o-) were cultured under static, physiological stretch (5% strain), or pathological excessive stretch (13% strain) conditions for 72 h. Conditioned media were collected and used to culture 16HBE14o- cells for 48 hours. Active and total TGF-β1 levels in the conditioned media were measured using an enzyme-linked immunosorbent assay. Cell viability, proliferation, migration, stress fiber formation, cell cycle distribution, and Smad2 signaling were assessed using the Cell Counting Kit-8 assay, cell counting, wound healing assay, immunofluorescence, flow cytometry, quantitative reverse transcription polymerase chain reaction, and Western blotting, respectively.</p><p><strong>Results: </strong>Conditioned media derived from ASMCs, but not 16HBE14o- cells, cultured under 13% excessive stretch inhibited 16HBE14o- cell proliferation. In addition, excessive stretch enhanced TGF-β1 activation in ASMCs in an integrin αV-dependent manner. Experiments using a TGF-β1-neutralizing antibody and transforming growth factor β receptor I inhibitors demonstrated that inhibition of 16HBE14o- cell proliferation by conditioned media derived from excessively stretched ASMCs was dependent on TGF-β1 activation and Smad2 signaling.</p><p><strong>Conclusion: </strong>Conditioned media derived from ASMCs, but not AECs, exposed to MV-associated excessive stretch induced G1 cell cycle arrest in AECs via TGF-β1/Smad2 signaling. These findings suggest that ASMCs are more sensitive than AECs to excessive stretch-induced TGF-β1 activation and may thereby contribute to disruption of airway epithelial integrity. Targeting this paracrine pathway may warrant further investigation as a potential strategy for preventing or treating VILI.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"55462"},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considerations for Predicting Peptides of the Insect Adipokinetic Hormone Ensemble Using Sequence Alignment.","authors":"Simone König","doi":"10.31083/FBL55493","DOIUrl":"https://doi.org/10.31083/FBL55493","url":null,"abstract":"<p><strong>Background: </strong>Adipokinetic hormones (AKHs) are metabolic regulators in insects, and many are still unknown. Bioinformatic analysis can assist entomologic research with predictions based on sequence similarity.</p><p><strong>Methods: </strong>AKHs are short peptides with specific sequence features, which were used together with the rules for preprohormone processing to interrogate National Center for Biotechnology Information (NCBI) genomic/transcriptomic data for novel putative AKH sequences by sequence alignment and similarity search. The structures of the signal peptide processing site and the dibasic processing site were evaluated in known and predicted AKHs.</p><p><strong>Results: </strong>28 novel AKHs were predicted, as well as 8 peptides likely belonging to the AKH/corazonin-related peptide family. Furthermore, the presence of 42 known AKHs was suggested in 162 species, which have not yet been investigated experimentally for such peptide hormones. The dibasic processing site in known AKHs was almost exclusively sequence tag GKR. For the signal peptide processing site, residues A/C/G/S/T/V were mostly found in the -3-position and A/C/G/S in the -1-position. The results were assembled in a searchable archive of validated (from the literature), predicted (obtained by sequence search), and hypothetical (from combinatorial calculation) amino acid sequences, including taxonomy criteria and mass information.</p><p><strong>Conclusions: </strong>The archive is a snapshot of the current AKH landscape and useful as a reference and research tool. It allows grouping and sorting the entries for, e.g., order-specific sequences or peptide ion <i>m</i>/<i>z</i> values, and thus assists, among other purposes, chemical analysis with hypotheses for the identification of hormones in newly investigated species. The systematic comparison of the observed structures of the processing sites helps in future sequence evaluations for predicted AKHs.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"55493"},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Transcriptomic and Functional Analyses Identify SERPINE1 as a Ferroptosis-Associated Mediator of Glioblastoma Radioresistance.","authors":"Yuhang Wang, Yanting Li, Meng Dong, Chao Zeng, Zhuanmei Jin, Qiuning Zhang, Wenzhen Yuan","doi":"10.31083/FBL53668","DOIUrl":"https://doi.org/10.31083/FBL53668","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Radiotherapy failure remains a major challenge in glioblastoma (GBM), yet the stress-adaptive programs that enable tumor cells to survive irradiation-induced lethal injury remain incompletely defined. This study investigated whether serpin family E member 1 (&lt;i&gt;SERPINE1&lt;/i&gt;) contributes to GBM radioresistance by modulating ferroptosis-associated lipid peroxidation, a process linked to iron-dependent oxidative injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Radiotherapy-treated GBM cohorts from TCGA (n = 93; 56 radiosensitive and 37 radioresistant cases), the Chinese Glioma Genome Atlas (CGGA)-325 (n = 100), and CGGA-693 (n = 193), as well as Clinical Proteomic Tumor Analysis Consortium (CPTAC) protein data and the Gene Expression Omnibus (GEO) single-cell RNA sequencing (scRNA-seq) dataset GSE131928, were analyzed using differential gene expression, weighted gene co-expression network analysis (WGCNA), machine-learning feature selection, FerrDb annotation, survival analysis, pathway enrichment, scRNA-seq, and tumor microenvironment (TME) signature profiling. Radiosensitive disease was defined as a complete or partial response after radiotherapy, whereas radioresistant disease was defined as stable or progressive disease. Statistical analyses included Wilcoxon rank-sum tests, Spearman correlations, log-rank tests, multivariable Cox regression for overall survival (OS), and time-dependent receiver operating characteristic (ROC) analysis. Functional validation was performed in two GBM cell lines (U87 and U251) using SERPINE1 knockdown or overexpression, X-ray irradiation, ferrostatin-1 (Fer-1), and RAS-selective lethal 3 (RSL3).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Integrative screening identified &lt;i&gt;SERPINE1&lt;/i&gt; as a ferroptosis-associated mediator of radioresistance and poor survival. &lt;i&gt;SERPINE1&lt;/i&gt; expression was elevated in primary GBM tumors (n = 199) compared with normal tissues (n = 18). &lt;i&gt;SERPINE1&lt;/i&gt;-high tumors showed enrichment of ferroptosis driver, suppressor, and marker gene signatures, consistent with a ferroptosis-stressed but ferroptosis-defensive state. Single-cell analysis localized &lt;i&gt;SERPINE1&lt;/i&gt; mainly to mesenchymal-like malignant cells, where high expression co-occurred with hypoxia, extracellular matrix remodeling, radioresistance, and ferroptosis-defense programs. In U87 cells, &lt;i&gt;SERPINE1&lt;/i&gt; knockdown enhanced radiosensitivity and increased irradiation-induced lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe&lt;sup&gt;2+&lt;/sup&gt; accumulation, whereas SERPINE1 overexpression in U251 cells attenuated ferroptosis-associated lipid peroxidation and iron accumulation and improved post-irradiation cell survival. Fer-1 partially rescued the radiosensitizing effect of &lt;i&gt;SERPINE1&lt;/i&gt; depletion, whereas RSL3 weakened &lt;i&gt;SERPINE1&lt;/i&gt;-mediated radioprotection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;&lt;i&gt;SERPINE1&lt;/i&gt; appears to link mesenchymal adaptation, redox stress regulation, and ferroptosis-associated l","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"53668"},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Drug-Tolerant Persister Cells in Cancer: Progress From Modeling to Targeting Fragility Studies.","authors":"Yanping Zheng, Xuqing Deng, Yufang Su, Jeremy R Chien, Meirong Liang","doi":"10.31083/FBL49637","DOIUrl":"https://doi.org/10.31083/FBL49637","url":null,"abstract":"<p><p>Drug-tolerant persister (DTP) cells are a major cause of cancer treatment failure and tumor relapse. This review provides a systematic summary of recent advances in research on DTP cells in cancer, including their biological features, model systems, and targeting strategies. Current studies show that formation of DTP cells is a complex and dynamic process, involving cell cycle arrest, epigenetic remodeling, and extensive transcriptional and metabolic reprogramming. The drug tolerance of DTP cells arises from a cooperative molecular network that integrates metabolic adaptation, reactivation of key signaling pathways, and resistance to cell death programs. To investigate the DTP state, researchers have developed a variety of <i>in vitro</i> and <i>in vivo</i> models, including patient-derived xenograft (PDX) models, drug-treated cancer cell lines, and organoid systems. These models have become essential tools for identifying vulnerabilities in DTP cells, such as sensitivity to ferroptosis induction, dependence on specific metabolic pathways, and expression of distinct surface antigens. However, the field still faces important challenges. Existing models have limitations in mimicking the complex tumor microenvironment and in capturing the transient nature of DTP cells. In addition, the clinical value of targeting strategies identified with experimental models remains to be validated in large-scale trials. The high level of heterogeneity of DTP cells and the lack of standardized research protocols also hinder the comparison and integration of findings across studies. The future development of more physiologically relevant models, the use of advanced technologies to better characterize DTP cells, and the design of clinical trials aimed at eliminating DTP cells are critical steps in the transition from tumor control to durable cure.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"49637"},"PeriodicalIF":3.1,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking Post-Traumatic Stress Disorder: A Systems-Level Disorder of Stress Dysregulation and the Role of Complementary and Alternative Medicine.","authors":"Eun Jin Yang, Hee Ra Park","doi":"10.31083/FBL55705","DOIUrl":"https://doi.org/10.31083/FBL55705","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is traditionally viewed as a brain-centered disorder characterized by impaired fear extinction and dysregulated emotional processing. Despite advances in pharmacologic and psychotherapeutic interventions, treatment resistance remains a major challenge for a substantial proportion of patients, highlighting the complexity of PTSD pathophysiology beyond central neural mechanisms. In addition, PTSD is associated with persistent dysregulation of systemic stress-regulatory networks, including the autonomic nervous system, immune-inflammatory pathways, and the gut-brain axis. This Opinion proposes that complementary and alternative medicine (CAM) interventions may exert therapeutic effects in PTSD by restoring disrupted homeostatic regulation across these interconnected systems. CAM modalities, such as acupuncture, herbal medicine, yoga, and breathing-based practices, may converge on common regulatory targets, including enhancement of vagal tone, modulation of inflammation, and stabilization of gut-brain communication. We propose that inconsistent clinical outcomes of CAM interventions in patients with PTSD may reflect, in part, inadequate patient stratification and outcome measures rather than an absence of therapeutic effects. Reconceptualizing PTSD as a disorder of systemic stress dysregulation provides a framework for investigating how CAM interventions might contribute mechanistically to an integrated, precision-oriented treatment paradigm.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"55705"},"PeriodicalIF":3.1,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nectin4 as a Promising Target for CAR-NK Cell Therapy in Breast Cancer Treatment.","authors":"Jianchun Lian, Xinyu Li, Tianlong Xu, Tingwei Zhu, Xin Huang, Cheng Wei, Ai Zhao, Jimin Gao","doi":"10.31083/FBL54654","DOIUrl":"https://doi.org/10.31083/FBL54654","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer continues to be a major global health burden, with a significant proportion of patients developing metastatic or treatment-resistant disease. Novel therapeutic strategies are urgently needed. Nectin cell adhesion molecule 4 (Nectin4), an adhesion molecule overexpressed in aggressive breast cancer subtypes, represents a promising target for immunotherapy due to its restricted expression in normal tissues. This study investigated the therapeutic potential of Nectin4-directed chimeric antigen receptor natural killer (CAR-NK) cell therapy against triple-negative breast cancer (TNBC) at the preclinical stage.</p><p><strong>Methods: </strong>Human natural killer (NK) cells obtained from peripheral blood from healthy donors were engineered to express an anti-Nectin4 chimeric antigen receptor (CAR) via lentiviral transduction, expanded <i>ex vivo</i>, and then used for functional studies. Cytotoxic activity was assessed <i>in vitro</i> against Nectin4-high-expressing breast cancer cells using luciferase-based killing assays at various effector-to-target ratios. <i>In vivo</i> efficacy was evaluated in NOD/SCID/IL2rγnull (NSG) mice bearing subcutaneous breast cancer tumors treated with CAR-NK cells, compared to untransduced NK cells and phosphate-buffered saline controls. Tumor growth was monitored using bioluminescence imaging and harvested tumors were subsequently analyzed for Nectin4 expression using immunohistochemistry.</p><p><strong>Results: </strong>CAR-NK cells potently and specifically lysed Nectin4-positive breast cancer cells <i>in vitro</i>, with up to 95% target cell lysis at an effector-to-target ratio of 5:1. <i>In vivo</i>, CAR-NK treatment reduced tumor burden and prolonged survival compared with controls. Immunohistochemical analysis revealed a marked reduction in Nectin4 expression within tumors from the CAR-NK-treated group, consistent with targeted tumor cell elimination.</p><p><strong>Conclusions: </strong>CAR-NK cells targeting Nectin4 demonstrated potent cytotoxic activity <i>in vitro</i> and effectively suppressed tumor growth <i>in vivo</i>, supporting the further evaluation of Nectin4 as a therapeutic target for CAR-NK-based immunotherapy in TNBC, particularly for aggressive subtypes with limited treatment options.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"54654"},"PeriodicalIF":3.1,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arhgap25 Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) by Driving Kupffer Cell Polarization via Activation of the AKT/mTOR Signaling Pathway.","authors":"Yan Wang, Shuangshuang Lu","doi":"10.31083/FBL53591","DOIUrl":"https://doi.org/10.31083/FBL53591","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading global health burden, yet the regulatory nodes linking hepatic immune dysregulation to metabolic perturbations remain incompletely understood.</p><p><strong>Methods: </strong>We integrated bulk and single-cell RNA sequencing (scRNA-seq) to identify core regulatory genes dysregulated by a high-fat diet (HFD). The functional role of the candidate gene Arhgap25, was validated using an adeno-associated virus (AAV)-mediated overexpression mouse model and an <i>in vitro</i> Kupffer cell (KC)-hepatocyte co-culture system.</p><p><strong>Results: </strong>Integrated transcriptomic analysis identified Arhgap25 as a key differentially expressed gene consistently upregulated in HFD-fed livers, with specific enrichment in KCs. <i>In vivo</i>, Arhgap25 overexpression significantly promoted macrovesicular steatosis, increased intrahepatic triglycerides and cholesterol levels, and exacerbated liver injury. Mechanistically, Arhgap25 triggered a pro-inflammatory microenvironment by promoting KC polarization toward the M1 phenotype, characterized by increased TNF-α, IL-6, and IL-1β expression and suppression of the M2 marker ARG1. <i>In vitro</i> co-culture assays demonstrated that Arhgap25 exacerbated hepatocellular lipid accumulation and inflammatory responses by promoting the phosphorylation of the AKT/mTOR signaling axis. AKT inhibition further confirmed this signaling dependency.</p><p><strong>Conclusion: </strong>Our findings establish Arhgap25 as a critical mediator in the hepatic immune-metabolic network. By positively regulating AKT/mTOR signaling in KCs, Arhgap25 promotes M1 polarization and subsequent metabolic dysfunction, highlighting it as a potential therapeutic target for MASLD.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"53591"},"PeriodicalIF":3.1,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SRPK Inhibition in Cholangiocarcinoma Cells Induces LAMB1-Associated Adaptive Responses and Enhances Growth Suppression by the MEK Inhibitor U0126 via the LAMB1/ERK/c-JUN Axis.","authors":"Chaturong Inpad, Prakasit Khamsuwan, Phuwapat Vongkaewpothong, Waritsara Susena, Kanyanut Kotanart, Tavan Janvilisri, Hathaichanok Impheng, Atit Silsirivanit, Sittiruk Roytrakul, Worasak Kaewkong","doi":"10.31083/FBL52847","DOIUrl":"https://doi.org/10.31083/FBL52847","url":null,"abstract":"<p><strong>Background: </strong>Cholangiocarcinoma (CCA) is an aggressive bile duct malignancy with a high incidence and mortality rate in Southeast Asia, particularly in Thailand. However, current treatments offer only limited clinical benefit. Aberrant mRNA splicing, driven by hyperactivation of serine/arginine-rich splicing factors (SRSFs) and their upstream kinases SRPK1 and SRPK2, contributes to the progression of CCA. Although SRPK inhibitors suppress tumor growth, their effects remain incomplete, highlighting the need for rational combination strategies.</p><p><strong>Methods: </strong>Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic profiling was performed on CCA cell lines (KKU-213A and KKU-055) treated with the SRPK inhibitors SRPIN340 and SPHINX31. Subsequently, commonly upregulated differentially expressed proteins (UpDEPs) were identified and cross-validated with data from the Cancer Genome Atlas (TCGA) using GEPIA, followed by reverse transcription-quantitative polymerase chain reaction (qRT-qPCR) validation. The functional effects of combined SRPK and mitogen-activated protein kinase kinase (MEK) inhibition (with U0126) were evaluated using cell viability and colony formation assays, and by analyzing signaling pathways.</p><p><strong>Results: </strong>A total of 34 common UpDEPs were identified following SRPK inhibition. Laminin subunit beta 1 (LAMB1) was prioritized as a candidate combination target due to robust upregulation, concordant overexpression in TCGA datasets, and increased mRNA levels after SRPK inhibitor treatment. Given prior evidence linking MEK signaling to LAMB1 regulation, we also evaluated the MEK inhibitor U0126. Combined treatment with SRPK inhibitors (SRPIN340 or SPHINX31) and U0126 produced greater suppression of viability and clonogenic growth in KKU-213A cells than either treatment alone. These effects were accompanied by reduced ERK phosphorylation and cellular Jun proto-oncogene (c-JUN) expression.</p><p><strong>Conclusions: </strong>LAMB1 represents a potential adaptive response target following SRPK inhibition in CCA. Dual targeting of SRPK and MEK signaling pathways exerts greater antitumor effects than either treatment alone and may provide a promising therapeutic strategy for CCA management.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"52847"},"PeriodicalIF":3.1,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}