Frontiers in Molecular Biosciences最新文献

{"title":"<i>In vitro</i> cytotoxic and pro-apoptotic effects of <i>Lactobacillus</i> rhamnosus GG cell-free supernatant on HT-29 colorectal cancer cells.","authors":"F Fareedhul Fahmitha, Manal Mowaffaq Mohammed, Prithviraj Karak, Estabraq Ali Hameed, Basim Mohammed Hanon, Israa M Essa, Hasanain A J Gharban, K Gayathri, P Saranraj, M Manigandan, Afsona Parveen, Sayandeep K Das","doi":"10.3389/fmolb.2026.1868859","DOIUrl":"https://doi.org/10.3389/fmolb.2026.1868859","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer is a leading cause of cancer-related mortality worldwide, underscoring the need for effective therapies with lower toxicity. Probiotic-derived metabolites (postbiotics) have emerged as promising anticancer components with immunomodulatory and antiproliferative effects.</p><p><strong>Methods: </strong>Cell-Free Supernatant (CFS) from <i>Lactobacillus rhamnosus</i> GG, produced under microaerophilic conditions and characterized by GC-MS, was tested against HT-29 colorectal adenocarcinoma cells. Cytotoxicity was evaluated by MTT assay, apoptosis following Annexin V-FITC/PI flow cytometry, and cell cycle distribution.</p><p><strong>Results: </strong>Growth under microaerophilic conditions yielded a sterile CFS that was subsequently profiled by GC-MS. Cytotoxicity was assessed by MTT assay, while apoptosis and cell-cycle distribution were evaluated by flow cytometry. GC-MS showed more than 65 chromatographic peaks, and 28 major compounds were tentatively identified by NIST-library matching; diketopiperazines accounted for approximately 45% of the total identified peak area. The study-strain CFS reduced HT-29 cell viability in a concentration-dependent manner, with an estimated IC50 of 14.2 micrograms/mL expressed as total lyophilized solids. Annexin V-FITC/PI flow cytometry showed 47.6 ± 2.9% early apoptotic, 2.3 ± 0.8% late apoptotic, 2.3 ± 0.6% necrotic, and 47.8 ± 3.2% viable cells after treatment. Treated cells were distributed as 47.3% G1, 38.9% S, 3.22% G2/M, and 2.60% sub-G1; because reliable quantitative control data were unavailable, phase-specific arrest could not be established.</p><p><strong>Conclusion: </strong>The study-strain CFS showed concentration-dependent in vitro cytotoxic and pro-apoptotic activity against HT-29 cells. The activity may be associated with the partial metabolite profile identified by GC-MS, but specific active compounds and molecular pathways were not established. The cell-cycle findings are descriptive because reliable quantitative control data were unavailable. Further studies using processed-medium controls, non-transformed colonic cells, additional cancer cell lines, orthogonal viability assays, mechanistic markers, and activity-guided fractionation are required.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1868859"},"PeriodicalIF":4.4,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106515","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":"Acute aerobic exercise is associated with a biphasic, temporally ordered shift in serum extracellular vesicle microRNA expression in major depressive disorder.","authors":"Beatriz B Elliott, Viraaj Vishnu Prasad, Alicia Taylor, Ian J Shofner, Karl Kerns, Jacob Meyer, Elizabeth M McNeill","doi":"10.3389/fmolb.2026.1910088","DOIUrl":"10.3389/fmolb.2026.1910088","url":null,"abstract":"<p><strong>Introduction: </strong>Acute aerobic exercise (AAE) is known to reduce symptoms of Major Depressive Disorder (MDD), yet the underlying biological mechanisms remain poorly understood. Here, we profiled microRNA (miRNA) expression within the serum extracellular vesicle (EV) enriched fraction (hereafter 'EV-enriched miRNA') of individuals diagnosed with MDD at multiple timepoints: before, during (mid), immediately after, and 75 min following a single 30-min session of moderate aerobic exercise. By characterizing the temporal dynamics of EV-enriched miRNA responses to AAE, our objective was to uncover molecular changes that may mediate exercise-induced molecular adaptations relevant to short- or long-term antidepressant effects of exercise and to identify candidate EV-enriched miRNAs for future mechanistic investigation of MDD.</p><p><strong>Methods: </strong>An EV-enriched serum fraction was isolated from a minimum of 28 individuals diagnosed with MDD. MicroRNA profiles were then assessed <i>via</i> RNA deep sequencing and analyzed with using DESeq2.</p><p><strong>Results: </strong>We identified time-dependent, significant (false discovery rate [FDR] ≤ 0.05) changes in EV-enriched microRNAs across AAE, with 15 differentially expressed at mid-AAE, 33 immediately post-AAE, and four at 75 min post-AAE. The response was biphasic and directional: miRNAs were predominantly downregulated during and immediately after exercise (13 of 15 down at mid-AAE; all 33 down post-AAE) and exclusively upregulated during recovery (all four up at 75 min post-AAE). hsa-miR-12523p was the only microRNA differentially expressed across all three postexercise timepoints, showing consistent downregulation. Functional enrichment of predicted targets of significantly differentially expressed miRNAs revealed a temporally ordered shift from RNA processing and stability at mid-AAE, to dendrite, synapse, and axon organization immediately post-AAE, to synaptic transmission and neuronal development at 75 min post-AAE.</p><p><strong>Discussion: </strong>AAE is associated with time-dependent, directional changes in EV-enriched microRNAs in MDD, whose predicted targets converge on synaptic plasticity pathways implicated in the disorder. Together, this suggests microRNAs may contribute to the beneficial short- and potentially long-term effects of aerobic exercise in individuals with MDD and provides specific targets for future mechanistic investigation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1910088"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079843","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":"Unravelling therapeutic resistance: role of cancer stem cell and microRNA in metastatic prostate cancer.","authors":"Hitakshi Moondra, Gautam Ram Choudhary, Dinesh Kumar Ahirwar, Mithu Banerjee, Surendra Kumar Shukla, Kamla Kant Shukla","doi":"10.3389/fmolb.2026.1904473","DOIUrl":"10.3389/fmolb.2026.1904473","url":null,"abstract":"<p><p>Metastatic prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men globally. This is largely attributable to the occurrence of therapeutic resistance that reduces the efficacy of the traditional treatment, such as Androgen deprivation therapy, chemotherapy, and radiotherapy. Accumulating evidence suggests that prostate cancer stem cells a rare population of Cancer Stem Cells drive therapy resistance by sustaining self-renewal, tumor plasticity, epithelial-mesenchymal transition, and metastasis. Concurrently, miRNAs are critical post-transcriptional regulators of gene expression, modulating key signalling pathways that control CSC stemness, reshaping tumor microenvironment, and conferring resistance to therapy. Dysregulation of miRNAs has been closely associated with the regulation of CSCs and the progression of metastatic PCa, and causes disease recurrence. In accordance with their targets, miRNAs can function either as oncogenic drivers that promote cancer progression or as tumor suppressors that inhibit malignant transformation and growth. Moreover, it contributes to the capacity of CSCs to withstand therapy and initiate disease recurrence. Recent advances in precision oncology have increased the pace of novel therapeutic modalities, such as CRISPR/Cas9, nanotechnology-based delivery vehicles, chimeric antigen receptor -T cell therapy, and epigenetic reprogramming strategies to counteract aberrant transcriptional states that sustain PCSC plasticity. The integration of these approaches offers a promising strategy to overcome refractoriness to treatment and improve clinical outcomes in advanced PCa. This review highlights the complex interplay between miRNAs and PCSCs in therapy resistance of metastatic PCa, and explores their translational potential in shaping durable and more effective clinical interventions.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1904473"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080075","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":"From hemodynamic stress to inflammatory wall remodeling in intracranial aneurysms.","authors":"Junzhe Zhu, Liuxun Hu, Mei Wu, Shiyu Shen, Yingjun Liu, Wei Zhu","doi":"10.3389/fmolb.2026.1893233","DOIUrl":"10.3389/fmolb.2026.1893233","url":null,"abstract":"<p><p>Intracranial aneurysms are dynamic diseases of the cerebrovascular wall whose growth and rupture cannot be fully explained by size, location, or morphology. Accumulating evidence indicates that aneurysm progression involves coordinated changes in hemodynamic exposure, endothelial phenotype, immune-cell infiltration, vascular smooth muscle cell function, and the extracellular matrix. This review examines how abnormal flow is translated into inflammatory wall remodeling, with particular emphasis on endothelial-myeloid interactions and their downstream effects on mural-cell and matrix homeostasis. Disturbed hemodynamic environments can promote endothelial inflammatory activation and monocyte recruitment, while recruited macrophages adopt heterogeneous functional states that contribute to sustained inflammation, vascular smooth muscle cell dysfunction, and proteolytic injury. Recent single-cell and spatial studies further reveal extensive endothelial, myeloid, and mural-cell heterogeneity within the aneurysm wall. Progressive loss of vascular smooth muscle cell reparative capacity and altered extracellular matrix turnover may ultimately compromise matrix organization and local load-bearing integrity. We also discuss how vessel wall imaging, computational hemodynamics, circulating biomarkers, and omics approaches may help characterize biologically active aneurysms. Together, these findings support a regional view of intracranial aneurysm progression in which mechanical, inflammatory, and structural processes interact within a heterogeneous vessel wall.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1893233"},"PeriodicalIF":4.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073963","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":"Radiomics machine learning model based on multi-sequence MRI for predicting Ki-67 expression level in glioblastoma.","authors":"Juan Ma, Palidanmu Wumaier, Gulijianaiti Maiamaituxun, Maiwulanjiang Amuti, Mireguli Damaola, Abudoumijiti Aji, Lijuan Da, Xin Qiao, Mayidili Nijiati, Diliaremu Aihaiti, Chunhui Jiang","doi":"10.3389/fmolb.2026.1876065","DOIUrl":"10.3389/fmolb.2026.1876065","url":null,"abstract":"<p><strong>Introduction: </strong>Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults, with median overall survival around 15 months. The Ki- 67 proliferation index is an important marker of proliferative activity and has prognostic relevance in GBM; however, its assessment requires surgical tissue and may be affected by sampling bias. Developing a non-invasive preoperative method to estimate Ki-67 expression may provide adjunctive information for risk assessment, while it should not be regarded as a stand-alone determinant of treatment decisions.</p><p><strong>Methods: </strong>This retrospective study included 269 histologically confirmed GBM patients from The Fourth Affiliated Hospital of Xinjiang Medical University. Patients were classified into low (n = 61) and high (n = 208) Ki-67 expression groups using a 20% threshold, selected according to published GBM Ki-67 stratification literature and local pathology reporting practice. Multi-sequence MRI scans were acquired at 3.0T, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR), and contrast-enhanced T1WI (CET1WI). A total of 8,612 radiomic features were extracted from three-dimensional tumor volumes across all sequences. After reducing dimensionality via Pearson correlation coefficient filtering and LASSO regression, machine learning models were built using BernoulliNB, GaussianNB, SVM, and AdaBoost classifiers for each sequence independently and a Combined model integrating all four sequences. Model performance metrics included AUC, accuracy, sensitivity, specificity, F1 score, calibration curves, and decision curve analysis (DCA). SHapley Additive exPlanations (SHAP) were used to interpret model predictions.</p><p><strong>Results: </strong>Baseline demographics (gender, BMI, age) did not differ significantly between groups. The Combined model integrating all sequences achieved the highest predictive accuracy, with AUCs of 0.915 (95% CI: 0.874-0.956) in the training set and 0.746 (95% CI: 0.614-0.879) in the test set, outperforming single-sequence models. Notably, the Combined model attained sensitivity of 0.930 and negative predictive value of 0.972 in training, indicating strong identification of high Ki-67 expression. Calibration curves and DCA demonstrated good model calibration and clinical utility.</p><p><strong>Discussion: </strong>A radiomics-based multi-sequence MRI machine learning model may serve as a non-invasive adjunct for preoperative Ki-67 estimation in GBM. The combined sequence approach outperformed single modalities, and SHAP analysis enhanced interpretability; however, clinical application requires external validation and outcome-based evidence before use in treatment decision-making.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1876065"},"PeriodicalIF":4.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073989","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":"TRIM2 suppresses prostate cancer progression by promoting ubiquitin-mediated degradation of DTNBP1.","authors":"Jiang He, Shen Liu, Wei Tong, Xiao Xiao, Maolin Xiao","doi":"10.3389/fmolb.2026.1945596","DOIUrl":"10.3389/fmolb.2026.1945596","url":null,"abstract":"<p><strong>Objective/background: </strong>Prostate cancer is the most commonly diagnosed malignancy in men worldwide, with high mortality rates and frequent metastasis at initial diagnosis, underscoring the need to elucidate its molecular mechanisms. TRIM2, an E3 ubiquitin ligase, plays critical roles in several cancers, but its function in prostate cancer remains unclear. This study aimed to investigate the expression, biological function, and clinical significance of TRIM2 in PCa progression.</p><p><strong>Methods: </strong>TRIM2 expression was analyzed using TCGA, GTEx, and GEO datasets, and validated in PCa and BPH tissues via qRT-PCR, western blot, and immunohistochemistry. Functional assays (CCK-8, wound healing, Transwell, flow cytometry) were performed in DU145 and PC-3 cells with TRIM2 overexpression or knockdown, and xenograft models assessed tumorigenicity in vivo. Proteomic sequencing combined with database prediction (UbiBrowser, BioGRID) identified DTNBP1 as a downstream substrate, confirmed by co-immunoprecipitation, ubiquitination assays, and cycloheximide chase. Drug sensitivity was evaluated using the GDSC database and molecular docking.</p><p><strong>Results: </strong>TRIM2 was significantly downregulated in PCa tissues, with the lowest levels observed in advanced and castration-resistant cases, and its reduced expression independently predicted worse progression-free interval. ROC analysis demonstrated that TRIM2 effectively discriminated localized from advanced/CRPC disease. TRIM2 overexpression significantly suppressed malignant behaviors <i>in vivo</i> and <i>vitro</i>. Mechanistically, TRIM2 directly interacted with DTNBP1 and promoted its ubiquitin-proteasome-mediated degradation. Drug sensitivity analysis and molecular docking revealed that TRIM2 expression serves as a predictor of PCa cell sensitivity to clinically relevant agents, including olaparib and navitoclax.</p><p><strong>Conclusion: </strong>Our findings establish the TRIM2-DTNBP1 axis as a key driver of PCa progression and position TRIM2 as a promising prognostic biomarker and a potential predictive indicator for guiding molecularly targeted therapies in advanced PCa.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1945596"},"PeriodicalIF":4.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074023","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":"Inhibition of the Sp1/CTR1 axis attenuates cuproptosis and alleviates axonal injury following intracerebral hemorrhage.","authors":"Ke Zhang, Wanyu Ma, Likun Wang, Guofeng Wu, Anjun Song, Siying Ren","doi":"10.3389/fmolb.2026.1932767","DOIUrl":"10.3389/fmolb.2026.1932767","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) causes severe neurological deficits, and secondary neuronal injury is a major barrier to recovery. Cuproptosis, a copper-dependent form of regulated cell death, has been linked to metabolic stress, but its role in axonal injury after ICH remains unclear. Here, we used <i>in vivo</i> rat ICH models and <i>in vitro</i> ICH-like neuronal injury models to examine changes in copper homeostasis, cuproptosis-associated molecular alterations, and axonal injury following ICH. Copper levels were markedly increased in perihematomal brain tissue and injured neurons, accompanied by reduced mitochondrial protein lipoylation and increased dihydrolipoamide S-acetyltransferase oligomerization, consistent with cuproptosis-associated molecular abnormalities. Specificity protein 1 (Sp1) and the copper transporter 1 (CTR1) were also significantly upregulated and showed similar temporal patterns. In parallel, ICH induced axonal injury-related molecular changes, including increased amyloid precursor protein and decreased growth-associated protein 43 expression. Pharmacological inhibition of Sp1 with plicamycin reduced CTR1 expression, attenuated copper overload, ameliorated cuproptosis-associated molecular abnormalities, and improved the measured axonal injury-related molecular and morphological changes <i>in vivo</i> and <i>in vitro</i>. These findings suggest that Sp1/CTR1-associated copper uptake regulation may contribute to secondary neuronal injury after ICH and may represent a potential therapeutic entry point for further investigation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1932767"},"PeriodicalIF":4.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074032","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":"Acidosis promotes exon skipping through sequestering SR-rich splicing factors in nuclear speckles.","authors":"Alina S Shtork, Pavel V Rubtsov, Anastasia N Kazakova, Iuliia I Pavlova, Olga M Ivanova, Sabina E Illarionova, Margarita E Bogomiakova, Svetlana V Sizova, Galina M Proshkina, Aleksandra A Strokach, Ksenia M Klimina, Victoria O Shender, Sergey M Deyev, Georgij P Arapidi, Anna M Varizhuk","doi":"10.3389/fmolb.2026.1862962","DOIUrl":"10.3389/fmolb.2026.1862962","url":null,"abstract":"<p><p>Deregulation of alternative splicing has long been associated with aggressive cancer phenotypes characterized by acute or chronic acidosis. Recently, it was hypothesized that this deregulation results from the sequestration of SR-rich splicing factors in nuclear speckles. However, this hypothesis lacked experimental evidence. Here, we demonstrate that, within the pH range consistent with acidosis, phosphorylated SR-rich fragments of splicing factors undergo a phase transition in minimal and multicomponent models of nuclear speckles. This acidification effect resembles the effect of SR dephosphorylation. We explain the molecular basis of this effect and visualize analogous transitions of nuclear speckles in acidified human cells. We also analyze splicing alterations in response to prolonged acidification. The most frequent alteration is exon skipping, consistent with the inaccessibility of SR-rich splicing factors, which normally promote exon inclusion. Our results support the previously proposed hypothesis and deepen the understanding of splicing regulation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1862962"},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149059767","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":"The mitochondrial DNA-cGAS-STING axis in colorectal cancer: a focused review of context-dependent roles and therapeutic opportunities.","authors":"Huayang Gui, Yali Zhang, Xingxing Yuan","doi":"10.3389/fmolb.2026.1939425","DOIUrl":"10.3389/fmolb.2026.1939425","url":null,"abstract":"<p><p>Immune checkpoint blockade produces durable benefit mainly in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC), whereas most microsatellite-stable/mismatch repair-proficient (MSS/pMMR) tumors remain poorly inflamed and resistant to immunotherapy. This focused narrative review examines how mitochondrial DNA (mtDNA)-derived danger signals engage the cGAS-STING pathway in CRC, distinguishes canonical DNA sensing from noncanonical STING activation and STING-independent cGAS functions, and evaluates therapeutic strategies that modulate this axis. We qualitatively synthesize peer-reviewed mechanistic and translational studies addressing mtDNA release, pathway routing, cellular context, therapeutic targeting, and biomarkers in CRC, while drawing on pan-cancer and DNA-damage studies only when they clarify pathway architecture or translational constraints. No new experimental, patient-level, or case-series data are presented. Current evidence indicates that biological outcome depends on more than pathway activation alone. Signal amplitude and duration, STING trafficking and proteostasis, downstream IRF3- versus NF-κB-biased signaling, autophagy and mitophagy, metabolic state, pathway abundance, and responding cell type collectively determine whether activation supports antitumor immunity or chronic inflammation and immune suppression. Nuclear DNA damage can also activate noncanonical STING programs independently of cGAS, whereas cGAS can exert STING-independent functions. Upstream mtDNA-origin interventions may provide a more localized route to pathway activation by exploiting tumor mitochondrial stress, but cGAS is not intrinsically mtDNA-specific and any safety advantage over direct STING agonism remains unproven clinically. Clinical translation should therefore prioritize origin-resolved biomarkers, cell-specific pharmacodynamic readouts, tumor-localized and transient pathway modulation, and biomarker-stratified trials.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1939425"},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149059769","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":"Beyond structures: solution NMR as the quantitative engine of integrated structural biology.","authors":"Jeffrey A Purslow, Vincenzo Venditti","doi":"10.3389/fmolb.2026.1941622","DOIUrl":"10.3389/fmolb.2026.1941622","url":null,"abstract":"<p><p>Structural biology is moving beyond the determination of static molecular structures toward quantitative descriptions of biomolecular mechanisms. Modern questions increasingly focus on conformational heterogeneity, exchange kinetics, weak and transient interactions, allostery, disorder, assembly, and phase behavior. These properties are often difficult to infer from crystallography, cryo-electron microscopy, scattering, imaging, mass spectrometry, molecular simulations, or structural prediction alone. Solution NMR spectroscopy occupies a distinctive position in this integrated landscape because it provides residue- and atom-specific observables that report on structure, dynamics, populations, kinetics, and interactions directly in solution. Here, we review the role of solution NMR in integrated structural biology from a question-centered perspective. Rather than organizing the discussion around individual NMR experiments, we ask how NMR can be used with complementary approaches to address recurring mechanistic problems: What is the structure of a biomolecule in solution? What conformational states are populated, and how rapidly do they interconvert? How do ligands, nucleic acids, membranes, surfaces, or partner proteins bind? How are allosteric signals transmitted? How do disorder, large assemblies, and biomolecular condensates regulate function? How can NMR observables be integrated with simulations and other structural restraints to build testable models? The future of solution NMR lies not primarily in isolated structure determination, but in its ability to transform structural models into dynamic, quantitative, and experimentally constrained descriptions of biomolecular mechanism.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1941622"},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149059835","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}