Frontiers in bioscience (Landmark edition)最新文献

{"title":"Association of c-Myc and Immune Cell Infiltration in Small Cell Lung Carcinoma.","authors":"Peiyan Zhao, Hui Li, Xinyue Wang, Na Di, Yan Liu, Lin Tian, Rui Zhong, Changlin Liang, Haifeng Liu","doi":"10.31083/FBL52899","DOIUrl":"https://doi.org/10.31083/FBL52899","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung carcinoma (SCLC) is a highly aggressive, rapidly proliferating malignancy largely corresponding to immune-cold tumor type. The role of the key oncogene c-Myc in regulating the complex immune microenvironment of SCLC remains unknown.</p><p><strong>Methods: </strong>Immunohistochemistry and multiplex immunofluorescence techniques were used to analyze c-Myc expression and immune cell infiltration. c-Myc and β-catenin expression were analyzed using western blotting. Flow cytometry was used to quantify the expression of immunosuppressive ligands-including programmed death ligand 1 (PD-L1), CD47, CD155, and human leukocyte antigen-E (HLA-E)-and characterize the function of T cells and macrophages. Cytokine levels were evaluated using enzyme-linked immunosorbent assays.</p><p><strong>Results: </strong>c-Myc expression in high tumor-infiltrating lymphocyte infiltration (TIL^high) tumor exceeded that in TIL^low tumors (<i>n</i> = 24) and was positively correlated with CD163⁺ macrophage infiltration (<i>p</i> = 0.0180). Immunosuppressive ligands were universally expressed on SCLC cells. 10058-F4-a c-Myc inhibitor-substantially downregulated the expression of PD-L1, CD47, and CD155 and upregulated HLA-E expression. In the coculture system, the inhibition of c-Myc in SCLC cells significantly upregulated interferon-gamma production in Jurkat cells, inhibited macrophage phagocytosis, and decreased cytokine concentrations in the supernatant. Further mechanistic studies revealed that c-Myc inhibition modulated the Notch signaling pathway and reduced the expression of E-cadherin, vascular endothelial (VE)-cadherin, and β-catenin. A β-catenin agonist improved the regulatory effect of 10058-F4 on the immunosuppressive ligands in SCLC cells.</p><p><strong>Conclusions: </strong>c-Myc expression in SCLC is associated with immune infiltration and may regulate the expression of immune-related ligands on SCLC cells via WNT/β-catenin signaling.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52899"},"PeriodicalIF":3.1,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889540","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":"PDLIM2 Promotes Osteogenesis of Adipose-Derived Stem Cells by Modulating β-Actin-Dependent Wnt/β-Catenin Signaling.","authors":"Yulian Shi, Tingyu Fan, Rongmei Qu, Guosheng Wu, Xiangtian Li, Jiaxuan Liu, Ziyi Feng, Haopeng Wu, Jun Ouyang, Jingxing Dai","doi":"10.31083/FBL52931","DOIUrl":"https://doi.org/10.31083/FBL52931","url":null,"abstract":"<p><strong>Background: </strong>Bone tissue possesses strong regenerative potential, but large segmental bone defects often exceed its intrinsic capacity for self-healing. Human adipose-derived stem cells (hASCs) offer a promising cellular basis for bone regeneration owing to their robust osteogenic differentiation potential. However, the role of PDZ and LIM domain 2 (PDLIM2) play in hASC osteogenesis and its relationship with the Wnt/β-catenin signaling pathway remain poorly understood.</p><p><strong>Methods: </strong>Western blotting, immunofluorescence staining, Alizarin Red S staining, alkaline phosphatase activity assays, wound healing assays, and Transwell assays were employed to assess osteogenic differentiation, osteogenic capacity, and cellular migration. Lentivirus-mediated PDLIM2 knockdown, cytochalasin D (CytoD) intervention, microfilament stabilizer treatment, and β-catenin activator treatment were used as a means of validating the regulatory mechanism.</p><p><strong>Results: </strong>hASCs exhibited the ability to undergo osteogenic differentiation. During this osteogenic process, significant increases in PDLIM2, β-actin, and β-catenin expression were observed, with PDLIM2 expression reaching 2-3 times that of the control group on day 14, whereas β-actin and β-catenin levels peaked on day 7 (1.5-2 times those in the control group). Lentivirus-mediated PDLIM2 knockdown reduced β-actin expression by approximately 5-fold and β-catenin expression by approximately 1.7-fold, accompanied by cytoskeletal disorganization and impaired osteogenic differentiation. Actin microfilament integrity was found to regulate osteogenic marker expression and alkaline phosphatase activity, while CytoD treatment suppressed β-actin and β-catenin expression to approximately 50% of control levels and inhibited osteogenic differentiation. Knocking down PDLIM2 attenuated the responsiveness of hASCs to microfilament stabilizers and β-catenin activators.</p><p><strong>Conclusions: </strong>This study demonstrates that PDLIM2 may be functionally associated with β-catenin nuclear translocation, potentially through the remodeling of the actin cytoskeleton. These findings provide preliminary mechanistic insight and warrant further validation.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52931"},"PeriodicalIF":3.1,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889516","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":"Chondrocyte Viability and Function is Impaired by E-Cigarette Liquid Flavor Additives.","authors":"Anzor Said, Connor Jaedicke, Mahika Ganguly, Amy Awadalla, Jessica A Cottrell","doi":"10.31083/FBL51207","DOIUrl":"https://doi.org/10.31083/FBL51207","url":null,"abstract":"<p><strong>Introduction: </strong>Environmental factors, such as inhaled chemical agents, may pose risks to cartilage tissue and embedded chondrocytes. Increasingly used among adolescents and young adults, electronic cigarettes (e-cigarettes) utilize aerosols rich in chemical flavoring agents that contact the respiratory epithelium and may adversely affect underlying airway structures, including chondrocyte-containing cartilage. This study evaluated the effect of common e-cigarette flavorings on chondrocyte viability and function using the ATDC5 cell line as a chondrocyte model.</p><p><strong>Methods: </strong>ATDC5 cells were exposed to increasing concentrations of nicotine-free e-cigarette liquid flavor additives (ELFAs) introduced into the media, followed by assessment of cellular metabolism, cellular membrane integrity, functional activity, inflammatory response, and gene expression profiling.</p><p><strong>Results: </strong>Significant cytotoxicity was observed in Cinnamon- and Menthol-treated groups, with near-complete loss of cell viability at concentrations ≥4%. These additives also induced dysregulation of chondrocyte matrix metabolism and increased expression of cyclo-oxygenase-2 activity, notably displaying significant upregulation of matrix metalloproteinase-13 (MMP-13) and prostaglandin E₂, respectively.</p><p><strong>Conclusions: </strong>Our findings show that commonly used ELFAs may alter chondrocyte metabolism, function, gene expression, and inflammatory signaling in a flavor‑ and concentration‑dependent manner, underscoring the need for deeper investigation into how e‑cigarette flavor additives affect cellular and tissue health.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"51207"},"PeriodicalIF":3.1,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889550","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":"Calcium Channel Blockers Modulate Calcium Homeostasis and Signaling Gene Expression in <i>Sophora tonkinensis</i>.","authors":"Ying Liang, Shuangshuang Qin, Guili Wei, Yuan Huang, Hong He, Fan Wei","doi":"10.31083/FBL54257","DOIUrl":"https://doi.org/10.31083/FBL54257","url":null,"abstract":"<p><strong>Background: </strong>Calcium signaling plays a critical role in plant growth, development, and stress adaptation. However, the tissue-specific mechanisms governing calcium homeostasis in medicinal plants adapted to high-calcium karst environments remain poorly understood. This study investigated the functional divergence and potential molecular basis of calcium homeostasis in leaves and root tips of <i>Sophora tonkinensis</i> under pharmacological perturbation.</p><p><strong>Methods: </strong>Treatments included lanthanum chloride (LaCl₃) (a plasma membrane Ca²⁺ channel blocker), sodium orthovanadate (Na₃VO₄) (a Ca²⁺-ATPase inhibitor), and ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (an extracellular Ca²⁺ chelator). Subcellular calcium distribution and expression of 14 calcium signaling-related genes were analyzed at 20, 40, and 60 days post-treatment using potassium pyroantimonate precipitation in conjunction with transmission electron microscopy and quantitative real-time PCR.</p><p><strong>Results: </strong>LaCl₃ treatment initially induced intracellular calcium accumulation, followed by the engagement of alternative efflux pathways in leaves and increased extracellular deposition in root tips. Na₃VO₄ treatment exacerbated intracellular calcium overload, resulting in sustained calcium toxicity in leaves, whereas root tips exhibited coordinated calcium redistribution. EGTA treatment dampened overall calcium signaling. However, root tips maintained functionality by mobilizing internal calcium stores. Gene expression analysis revealed a significant upregulation of <i>Sophora tonkinensis</i> calmodulin-like protein 9 (<i>StCML9</i>) in roots (up to 11.7-fold relative to the control), with expression closely synchronized with Ca²⁺ fluctuations, suggesting a potential role for <i>StCML9</i> in calcium sensing and adaptive responses. In contrast, <i>Sophora tonkinensis</i> calcium-dependent protein kinases (<i>StCDPKs</i>) were generally suppressed in leaves.</p><p><strong>Conclusions: </strong>These findings suggest that <i>S. tonkinensis</i> may employ organ-specific calcium distribution and transcriptional reprogramming to maintain calcium homeostasis under signaling perturbation. This study provides correlative evidence that contributes to mechanistic insights into the species' adaptation to high-calcium karst environments and offers candidate genes for future functional validation.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"54257"},"PeriodicalIF":3.1,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889545","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":"Metabolic Dysfunction-Associated Steatotic Liver Disease and Mitochondrial Quality Control: From Laboratory to Clinical Practice.","authors":"Wenkai Fu, Junqi Wang, Nan Lu, Zhijiang Guo, Sang-Bing Ong, Yong Gao, Hao Zhou, Xing Chang, Miao Meng","doi":"10.31083/FBL41721","DOIUrl":"https://doi.org/10.31083/FBL41721","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 1.66 billion people globally. This metabolic disorder shows strong connections with mitochondrial dysfunction and disrupted mitochondrial quality control (MQC) processes. Our review systematically analyzes the molecular mechanisms underlying the relationship between MQC and MASLD development. Research evidence indicates that impaired MQC regulation worsens three key pathological conditions: it intensifies liver fat accumulation, increases oxidative damage, and promotes inflammatory cell death through activating inflammatory signaling pathways, boosting reactive oxygen species generation, and triggering programmed cell death in hepatocytes. Current pharmacological interventions have shown mixed effects. Metformin, resveratrol, and empagliflozin have moderating effects on MQC homeostasis in experimental models, but their clinical application remains limited. The review further predicts two key systemic impacts of MASLD: it amplifies cardiovascular disease risk through links between organ systems, and it highlights the need to develop targeted regulation of the gut microbiota. Three major research challenges require urgent attention: first, clarifying the complex interactions between different MQC pathways; second, establishing clinical effectiveness through human trials; third, bridging the gap between laboratory findings and practical medical interventions. These priorities highlight the need for coordinated multidisciplinary research efforts to address this growing public health challenge.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"41721"},"PeriodicalIF":3.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889475","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":"Fucoidan: Modulating Post-Myocardial Infarction Inflammation via the Gut-Heart Axis.","authors":"Yuan Zou, Yingqi Li, Mowei Kong, Yang Yu","doi":"10.31083/FBL41364","DOIUrl":"https://doi.org/10.31083/FBL41364","url":null,"abstract":"<p><p>Myocardial infarction (MI) remains a major cause of global morbidity and mortality, with post-MI inflammation significantly exacerbating tissue damage and adverse cardiac remodeling. Recent advancements have highlighted the gut microbiota as a crucial regulator of cardiovascular health via the gut-heart axis. This review introduces a novel therapeutic perspective by exploring the potential mechanisms through which fucoidan, a sulfated polysaccharide derived from marine algae, may alleviate post-MI inflammation. Fucoidan demonstrates unique anti-inflammatory and antioxidant properties and has been shown to modulate the gut microbiota. Specifically, it enhances the abundance of beneficial gut bacteria, boosts short-chain fatty acids (SCFA) production, and reduces bacterial endotoxin translocation. Additionally, fucoidan directly inhibits inflammatory signaling pathways, decreases pro-inflammatory cytokine secretion, and protects cardiomyocytes through antioxidant effects. These multifaceted actions position fucoidan as a promising novel therapeutic strategy for mitigating post-MI inflammation and promoting cardiac recovery. Future research should focus on optimizing fucoidan extraction methods, identifying effective dosing regimens, and developing targeted delivery systems to maximize clinical efficacy.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"41364"},"PeriodicalIF":3.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889546","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":"Plasma Extracellular Vesicle Profiles After Heart Transplantation are Associated With the Type of Allograft Rejection.","authors":"Arthur Aquino, Lubov Korneva, Maria Osipova, Maria Bortsova, Maria Simonenko, Darina Sambur, Ivan Golovkin, Igor Kudryavtsev, Ekaterina Zaikova, Anna Kostareva, Olga Kalinina, Petr Fedotov, Alexey Golovkin","doi":"10.31083/FBL50478","DOIUrl":"https://doi.org/10.31083/FBL50478","url":null,"abstract":"<p><strong>Background: </strong>Heart transplantation (HT) remains the primary treatment for end-stage heart failure, but graft rejection-including acute cellular rejection (ACR), antibody-mediated rejection (AMR), and chronic rejection such as cardiac allograft vasculopathy (CAV)-significantly impacts long-term patient outcomes. This study investigates the role of circulating plasma extracellular vesicle profiles as potential biomarkers for distinguishing between different rejection types following HT.</p><p><strong>Methods: </strong>We enrolled 85 HT patients with post-transplant follow-up ranging from 2 to 140 months. The cohort included patients diagnosed with AMR (n = 23), ACR (n = 11), CAV (n = 20), and those without rejection (R0, n = 31). Extracellular vesicle profiles were analyzed using the MACSPlex Exosome Kit, and associated cytokine profiles were assessed using the MILLIPLEX Human Cytokine Panel A. Statistical analysis involved the Kruskal Wallis test followed by Dunn's post-hoc test for multiple comparisons and discriminant analysis.</p><p><strong>Results: </strong>Circulating plasma extracellular vesicle profiles demonstrated significant differences across post-transplantation time strata and varied according to the type of transplant rejection. During the first year post-HT, the main discriminant factors were extracellular vesicles (EVs) characterized by tetraspanins (CD9+, CD63+) and platelet markers (CD62P+, CD42a+). Five years post-transplantation, significant differences emerged in patients with AMR and ACR (both compared to each other and to the CAV/R0 groups). This difference corresponded with an increase in EV markers associated with immune cell activity (CD3+, CD4+, CD49e+, CD86+, CD20+, CD14+, CD209+, CD1c+, CD29+). Levels of prominent EV subpopulations correlated with IL‑22 in CAV patients, whereas in AMR patients, they correlated with IL‑17 and IL‑25.</p><p><strong>Conclusions: </strong>These findings support the hypothesis that extracellular vesicles may participate in both direct and indirect antigen presentation and in the regulation of immune responses leading to allograft rejection after HT. Plasma extracellular vesicle profiles hold promise as non-invasive biomarkers for monitoring and differentiating rejection types in heart transplant recipients.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"50478"},"PeriodicalIF":3.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889529","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":"Alzheimer's Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System.","authors":"Balazs Sonkodi","doi":"10.31083/FBL52555","DOIUrl":"https://doi.org/10.31083/FBL52555","url":null,"abstract":"<p><p>Alzheimer's disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer's disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP₂) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer's disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP₂ is emerging as a potential treatment method for Piezo channelopathy in Alzheimer's disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52555"},"PeriodicalIF":3.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889503","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":"Septic Cardiomyopathy and Mitochondrial Quality Control.","authors":"Xiangyi Pu, Zhaoqi Yan, Zhiming Liu, Xing Chang, Ruxiu Liu","doi":"10.31083/FBL47390","DOIUrl":"https://doi.org/10.31083/FBL47390","url":null,"abstract":"<p><p>Septic cardiomyopathy (SCM) is a prevalent and serious cardiac complication arising from sepsis-induced multiple organ dysfunction syndrome (MODS). The pathogenesis of SCM is complex and primarily involves immune-inflammatory responses, oxidative stress, programmed cell death, and mitochondrial dysfunction. In recent years, mitochondrial quality control (MQC) has attracted growing interest as a central mechanism for maintaining cellular homeostasis and myocardial energy metabolism in SCM. This review systematically summarizes recent advances in four key MQC mechanisms involved in SCM: (1) phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy; (2) mitochondrial dynamics, including dynamin-related protein 1 (Drp1)/fission protein 1 (FIS1)-driven fission and optic atrophy protein 1 (OPA1)/mitofusin (MFN)-regulated fusion; (3) mitochondrial biogenesis under the regulatory control of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) axis; and (4) the mitochondrial unfolded protein response (UPRmt), which maintains mitochondrial proteostasis through mediators such as C/EBP homologous protein (CHOP), YME1-like protease (YME1L), and Overlapping activity with m-AAA protease 1 (OMA1). These mechanisms have been shown to work synergistically to regulate mitochondrial clearance, renewal, and functional maintenance. Any imbalance among them can exacerbate myocardial injury. This review also emphasizes the redox crosstalk between oxidative stress and immune inflammation, with an emphasis on the pivotal contributions of NADPH oxidase 2 (NOX2), high mobility group box 1 (HMGB1), and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in vascular endothelial dysfunction and cardiac depression. In conclusion, preserving the dynamic equilibrium of MQC is crucial for preventing or reversing SCM and may present novel molecular targets and therapeutic strategies.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"47390"},"PeriodicalIF":3.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889574","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":"IFIT1⁺ Tumor-Associated Macrophages Suppress Cancer Stemness and Enhance Chemosensitivity via the TNFSF10-TNFRSF10B Axis in Epithelial Ovarian Cancer.","authors":"Rui Liu, Yilin Fang, Ruxi Zheng, Liya Lin, Da Huang, Lingyun Zhai, Qionghua He, Zhigang Zhang, Jianwei Zhou, Xiaoming Zhang","doi":"10.31083/FBL52801","DOIUrl":"https://doi.org/10.31083/FBL52801","url":null,"abstract":"<p><strong>Background: </strong>Epithelial ovarian cancer (EOC) is typically diagnosed at an advanced stage and is associated with high mortality due to metastasis and chemoresistance. Cancer stem cells (CSCs) are central to EOC progression, recurrence, and treatment resistance, with their functional behavior shaped by the tumor immune microenvironment. While M1 and M2 macrophages have been well-characterized, the role of interferon-stimulated gene-enriched subpopulations, particularly interferon-induced protein with tetratricopeptide repeats 1 tumor-associated macrophages (IFIT1⁺ TAMs), in regulating CSC properties in EOC remains largely unexplored.</p><p><strong>Methods: </strong>Single-cell RNA sequencing (scRNA-seq) was utilized to map the myeloid landscape and trace transcriptomic evolution in EOC. An <i>in vitro</i> indirect culture model utilizing unpolarized macrophage (M0)-conditioned medium (CM) was established to assess baseline phenotypic alterations. Furthermore, targeted siRNA silencing (si-<i>TNFRSF10B</i>) combined with recombinant human tumor necrosis factor ligand superfamily member 10 (TNFSF10) (rhTRAIL) treatments were employed to evaluate the specific impact of the TNF-related apoptosis-inducing ligand (TRAIL)-Death receptor 5 (DR5) signaling axis on multidrug resistance and CD44 expression.</p><p><strong>Results: </strong>High-resolution scRNA-seq analysis revealed a stage-dependent decline in IFIT1⁺ TAMs, an interferon-primed subset that robustly expresses the TNFSF10 ligand during early-stage disease. <i>In vitro</i> assays showed that conditioned medium from M0 macrophages suppresses CSC features and enhances expression of the tumor necrosis factor receptor superfamily member 10B (Death receptor 5) (TNFRSF10B/DR5) in EOC cells. Mechanistic studies confirmed that exogenous rhTRAIL treatment markedly diminished CD44⁺ cell populations and enhanced sensitivity to chemotherapeutic agents. Notably, these antitumor effects were largely abrogated following siRNA-mediated silencing of the DR5 receptor in EOC cell lines.</p><p><strong>Conclusions: </strong>Our findings reveal that IFIT1⁺ tumor-associated macrophages intrinsically harbor anti-cancer stem cell potential through the TNFSF10 ligand. Activation of the TNFSF10-TNFRSF10B pathway suppresses cancer stemness and may enhance chemosensitivity. These insights shed light on the functional diversity of macrophages, highlighting that driving tumor-associated macrophages toward a sustained, interferon-primed IFIT1⁺ phenotype represents a promising therapeutic approach to target cancer stem cell populations in epithelial ovarian cancer.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52801"},"PeriodicalIF":3.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889590","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}