{"title":"Role of the cytoskeleton in cellular reprogramming: effects of biophysical and biochemical factors.","authors":"Ekaterina Momotyuk, Nour Ebrahim, Ksenia Shakirova, Erdem Dashinimaev","doi":"10.3389/fmolb.2025.1538806","DOIUrl":"10.3389/fmolb.2025.1538806","url":null,"abstract":"<p><p>The cytoskeleton plays a crucial role in regulating cellular behavior, acting as both a structural framework and a mediator of mechanical and biochemical signals that influence cell fate. In the context of cellular reprogramming, modifications to the cytoskeleton can have profound effects on lineage commitment and differentiation efficiency. This review explores the impact of mechanical forces such as substrate stiffness, topography, extracellular fluid viscosity, and cell seeding density on cytoskeletal organization and mechanotransduction pathways, including Rho/ROCK and YAP/TAZ signaling. Additionally, we examine the influence of biochemical agents that modulate cytoskeletal dynamics, such as actin and microtubule polymerization inhibitors, and their effects on stem cell differentiation. By understanding how cytoskeletal remodeling governs cellular identity, this review highlights potential strategies for improving reprogramming efficiency and directing cell fate by manipulating mechanical and biochemical cues.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1538806"},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691575","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":"Exploring proinsulin proteostasis: insights into beta cell health and diabetes.","authors":"Parisima Ghaffarian Zavarzadeh, Kathigna Panchal, Dylan Bishop, Elizabeth Gilbert, Mahi Trivedi, Tovaria Kee, Srivastav Ranganathan, Anoop Arunagiri","doi":"10.3389/fmolb.2025.1554717","DOIUrl":"10.3389/fmolb.2025.1554717","url":null,"abstract":"<p><p>Proinsulin misfolding is central to diabetes. This review examines the cellular mechanisms regulating proinsulin proteostasis in pancreatic β-cells, encompassing genetic factors such as insulin gene mutations, and exploring the roles of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), ER redox balance, mitochondrial function, and the influence of extrinsic factors. Mutations in the INS gene, particularly those affecting cysteine residues, impair folding and disulfide bond formation, often exhibiting dominant-negative effects on the wild-type proinsulin. The importance of ER quality control mechanisms, including chaperones and oxidoreductases, in facilitating proper folding and degradation of misfolded proinsulin is emphasized. Disruptions in these systems, due to genetic mutations, ER stress, or impaired ER-to-Golgi trafficking, lead to proinsulin accumulation and β-cell dysfunction. The unfolded protein response (UPR), especially the PERK and IRE1α-XBP1 pathways, emerges as a central regulator of protein synthesis and ER stress management. The review also discusses the role of mitochondrial health, ER redox state, and extrinsic factors such as diet and medications in influencing proinsulin proteostasis. Finally, the structural insights from NMR and molecular dynamics simulations are discussedhighlighting the dynamics of misfolding and underscoring the importance of disulfide bonds. These mechanistic insights suggest innovative strategies targeting thiol/disulfide redox systems in cells to mitigate protein misfolding diseases including diabetes.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1554717"},"PeriodicalIF":3.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663139","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":"Carbon dots derived from <i>Zingiber officinale</i> Rosc (ginger) with hemostatic effects.","authors":"Wen-Jing Hu, Ai-Qi Yu, Hai-Zheng Bi, Zhao-Jiong Zhang, Zhi-Bin Wang, Meng Wang, Hai-Xue Kuang","doi":"10.3389/fmolb.2025.1530469","DOIUrl":"10.3389/fmolb.2025.1530469","url":null,"abstract":"<p><strong>Introduction: </strong>Ginger, as a traditional Chinese medicine (TCM), can be used in clinical practice to treat various diseases. The product of ginger processed at high temperatures is called carbonized ginger (CG), which has a hemostatic effect that ginger originally did not have. The purpose of this study is to investigate the hemostatic effect of CG and the substances that exert hemostatic effects.</p><p><strong>Methods: </strong>CG was prepared and successfully obtained CG carbon dots (CG-CDs) from its aqueous solution. After fully characterizing its structural information, the hemostatic effect was evaluated using mouse tail bleeding and liver injury bleeding models, and the clotting time was evaluated using capillary coagulation experiments. In addition, the hemostatic mechanism of CG-CDs was explored.</p><p><strong>Results: </strong>The average particle size of CG-CDs was observed to be 4.07 nm and the lattice spacing was 0.216 nm. It was mainly composed of graphite structured carbon, with the main constituent elements being C, N, and O, containing functional groups such as C=N, C=O, and C-OH. The FL spectrum showed that the maximum excitation wavelength of CG-CDs was 360 nm, and the maximum emission wavelength was 470 nm. The QY of CG-CDs was calculated to be 0.45%. CG-CDs shortened bleeding time, reduced bleeding volume, and also shortened the time for blood clotting. With the increase of CG-CDs, the values of FIB gradually increased, and the PT values gradually decreased. In addition, CG-CDs increased PLT count, increased PLT activating factor TXB2, decreased 6-keto-PGF<sub>1<i>α</i></sub> , increased PAI-1, and decreased t-PA.</p><p><strong>Conclusion: </strong>CG-CDs obtained from CG has hemostatic activity, mainly by activating exogenous coagulation and co-coagulation pathways, increasing PLT count, increasing PLT activating factor TXB2, reducing 6-keto-PGF<sub>1<i>α</i></sub> , increasing PAI-1, and reducing t-PA, thereby affecting the fibrinolytic system and other pathways to exert hemostatic effects.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1530469"},"PeriodicalIF":3.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656839","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}
Yufeng Xie, Yun Chen, Ting Qin, Jun Li, Zhichun Chang, Yanfang Li, Jianmei Zhang, Mujun Liu, Jianli Wang, Rong Ren, Ziliang Qian, Jinxin Liu, Min Chen
{"title":"Moxibustion inhibits inflammation in monosodium urate crystal-induced gouty arthritis model rats through metabolomic regulation.","authors":"Yufeng Xie, Yun Chen, Ting Qin, Jun Li, Zhichun Chang, Yanfang Li, Jianmei Zhang, Mujun Liu, Jianli Wang, Rong Ren, Ziliang Qian, Jinxin Liu, Min Chen","doi":"10.3389/fmolb.2025.1433912","DOIUrl":"10.3389/fmolb.2025.1433912","url":null,"abstract":"<p><strong>Background: </strong>Moxibustion is a form of therapy that to warm the acupoints located skin by using dried mugwort leaves. It is widely used to treat gouty arthritis (GA). However, the mechanism of moxibustion on improving GA has not been fully revealed. In this study, we explore the mechanism of moxibustion on GA via metabolomics combined with traditional Chinese medicine (TCM) theory.</p><p><strong>Methods: </strong>Three days before model induction, the rats of moxibustion groups were treated with moxibustion in the ST36 and SP6, and then, a GA rat model induced by monosodium urate (MSU) was established. Biological samples, including joint synovial tissue and serum samples, were collected and measured by histopathological staining, molecular biology assays and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics.</p><p><strong>Results: </strong>We found that moxibustion could reduce the ankle edema induced by MSU crystals, decrease the expression of related proinflammatory genes, decrease the levels of serum IL-18 and IL-1β, and restore the metabolism of glycerol phospholipids, niacin and nicotinamide in GA model rats.</p><p><strong>Conclusion: </strong>Moxibustion can regulate the metabolism of GA model rats widely to inhibit inflammation. Our research deepens our understanding of the complex mechanisms of moxibustion and promotes the application of moxibustion in the clinical practice.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1433912"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647787","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}
Mingjing Meng, Jiani Wang, Jiumei Yang, Yangming Zhang, Xusheng Tu, Pan Hu
{"title":"PRR13 expression as a prognostic biomarker in breast cancer: correlations with immune infiltration and clinical outcomes.","authors":"Mingjing Meng, Jiani Wang, Jiumei Yang, Yangming Zhang, Xusheng Tu, Pan Hu","doi":"10.3389/fmolb.2025.1518031","DOIUrl":"10.3389/fmolb.2025.1518031","url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer continues to be a primary cause of cancer-related mortality among women globally. Identifying novel biomarkers is essential for enhancing patient prognosis and informing therapeutic decisions. The PRR13 gene, associated with taxol resistance and the progression of various cancers, remains under-characterized in breast cancer. This study aimed to investigate the role of PRR13 in breast cancer and its potential as a prognostic biomarker.</p><p><strong>Methods: </strong>We performed a comparative analysis of PRR13 gene expression utilizing the TCGA database against non-cancerous tissues and employed STRING to evaluate PRR13's protein-protein interactions and associated pathways. Additionally, we investigated the relationship between PRR13 mRNA expression and immune cell infiltration in breast cancer (BRCA) using two methodologies. Furthermore, a retrospective analysis of 160 patients was conducted, wherein clinical data were collected and PRR13 expression was evaluated through immunohistochemistry and qRT-PCR to determine its association with clinicopathological features and patient survival.</p><p><strong>Results: </strong>Analysis of the TCGA database revealed significant upregulation of PRR13 expression across 12 different cancer types, including breast cancer. High PRR13 expression was positively correlated with various immune cells, including NK cells, eosinophils, Th17 cells, and mast cells, whereas a negative correlation was observed with B cells, macrophages, and other immune subsets. Enrichment analysis of PRR13 and its 50 interacting proteins revealed significant associations with biological processes such as cell adhesion and migration, and pathways including ECMreceptor interaction and PI3K-Akt signaling. Single-cell analysis demonstrated associations between PRR13 and pathways pertinent to inflammation and apoptosis. Validation studies confirmed elevated PRR13 expression in tumor tissue compared to adjacent non-cancerous tissue. Immunohistochemistry demonstrated high PRR13 expression in 55.6% of cancer cases, particularly associated with advanced clinical stage and lymph node metastasis. Moreover, high PRR13 expression significantly correlated with shorter overall survival and served as an independent prognostic factor. Subgroup analysis underscored the prognostic significance of PRR13 in aggressive tumor subtypes, with particularly strong associations observed in T3, N1-3, and moderately to poorly differentiated tumors.</p><p><strong>Discussion: </strong>In conclusion, PRR13 expression is upregulated in breast cancer tissues and may serve as a valuable prognostic indicator for breast cancer patients, potentially impacting patient survival and therapeutic strategies.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1518031"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647792","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":"Chromatin structure and gene transcription of recombinant p53 adenovirus vector within host.","authors":"Duo Ning, Yuqing Deng, Simon Zhongyuan Tian","doi":"10.3389/fmolb.2025.1562357","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1562357","url":null,"abstract":"<p><strong>Introduction: </strong>The recombinant human p53 adenovirus (Ad-p53) offers a promising approach for cancer therapy, yet its chromatin structure and effects on host chromatin organization and gene expression are not fully understood.</p><p><strong>Methods: </strong>In this study, we employed <i>in situ</i> ChIA-PET to investigate the colorectal cancer cell line HCT116 with p53 knockout, comparing them to cells infected with the adenovirus-vector expressing p53. We examined alterations in chromatin interactions and gene expression following treatment with the anti-cancer drug 5-fluorouracil (5-FU).</p><p><strong>Results: </strong>Our results indicate that Ad-p53 forms a specific chromatin architecture within the vector and mainly interacts with repressive or inactive regions of host chromatin, without significantly affecting the expression of associated genes. Additionally, Ad-p53 does not affect topologically associating domains (TADs) or A/B compartments in the host genome.</p><p><strong>Discussion: </strong>These findings suggest that while Ad-p53 boosts p53 expression, enhancing drug sensitivity without substantially altering host HCT116 chromatin architecture.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1562357"},"PeriodicalIF":3.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647773","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}
Chiara Baggio, Paola Galozzi, Amelia Damasco, Vanni Lazzarin, Giampietro Ravagnan, Paolo Sfriso, Roberta Ramonda, Leonardo Punzi, Gianmaria Pennelli, Andrea Doria, Roberto Luisetto, Francesca Oliviero
{"title":"Multitargeted biological actions of polydatin in preventing pseudogout acute attack.","authors":"Chiara Baggio, Paola Galozzi, Amelia Damasco, Vanni Lazzarin, Giampietro Ravagnan, Paolo Sfriso, Roberta Ramonda, Leonardo Punzi, Gianmaria Pennelli, Andrea Doria, Roberto Luisetto, Francesca Oliviero","doi":"10.3389/fmolb.2025.1553912","DOIUrl":"10.3389/fmolb.2025.1553912","url":null,"abstract":"<p><strong>Introduction: </strong>We have recently shown that polydatin (PD) prevents calcium pyrophosphate (CPP) crystal-induced arthritis in mice. This study aims to explore potential mechanisms of action associated with this anti-inflammatory effect.</p><p><strong>Materials and methods: </strong>Acute arthritis was induced in Balb/c mice by the injection of crystals into the ankle joint. Animals were randomised to receive PD or colchicine according to a prophylactic protocol. Ankle swelling was measured and both joints and muscles were harvested at sacrifice. Histological evaluations were performed using H&E staining to assess cartilage and muscle damage. Kondziela's inverted test was used to assess muscle strength. An exploratory protein array was performed on joint tissue to identify relevant inflammatory pathways. Human monocytes pretreated with PD were stimulated with CPP crystals. The use of specific inhibitors was instrumental in demonstrating their anti-inflammatory effects and assessing the role of SIRT1. The chemotaxis assay was performed to test the effect of PD and J-113863 on PBMCs migration in response to plasma and synovial fluids. Cytokine levels were measured by ELISA.</p><p><strong>Results: </strong>CPP crystals injection resulted in swelling, leukocyte infiltration, loss of synovial membrane structure homogeneity. Mice pretreated with PD showed reduced ankle swelling and this was associated with very limited inflammatory damage. Regarding the effect on gastrocnemius muscle, crystals induced leukocyte infiltration and edema. PD and colchicine treatment reduced muscle damage and preserved musculoskeletal structure in mice. The cytokine array revealed the activation of various inflammatory pathways after CPP injection and PD was shown to influence leukocyte migration, angiogenesis and inflammation. <i>In vitro</i>, PD reduced inflammatory cytokines, chemokines and VEGF levels. CCR-1 inhibition was effective in reducing pro-inflammatory mediator levels in CPP treated monocytes and in reducing PBMCs migration. The anti-inflammatory action of PD also involved SIRT-1 activation, and its inhibition reverted the beneficial effects of PD. Finally, PD reduced the PBMCs migration in response to synovial fluids.</p><p><strong>Conclusion: </strong>PD effectively prevents inflammatory responses to CPP crystals in mice, preserving both articular and muscular structures. Its anti-inflammatory effects are primarily mediated through pathways regulating leukocyte migration and the suppression of pro-inflammatory mediators.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1553912"},"PeriodicalIF":3.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624156","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":"Editorial: Role of fibroblast in cancer.","authors":"Xuezhen Zeng, Man Liu","doi":"10.3389/fmolb.2025.1574538","DOIUrl":"10.3389/fmolb.2025.1574538","url":null,"abstract":"","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1574538"},"PeriodicalIF":3.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624153","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}
Maria Cristina Mazzarella, Stefano Cristiano, Dilia Rea, Nicola Mazzarella, Martina Addeo, Silvia Iannelli, Geppino Falco, Mariarita Brancaccio, Tiziana Angrisano
{"title":"Pilot study: a descriptive-retrospective analysis of SARS-CoV-2 variants distribution and phylogenesis in the Phlegraean area.","authors":"Maria Cristina Mazzarella, Stefano Cristiano, Dilia Rea, Nicola Mazzarella, Martina Addeo, Silvia Iannelli, Geppino Falco, Mariarita Brancaccio, Tiziana Angrisano","doi":"10.3389/fmolb.2025.1536953","DOIUrl":"10.3389/fmolb.2025.1536953","url":null,"abstract":"<p><p>COVID-19 disease, caused by SARS-CoV-2 virus, marked the pandemic era, opening the way to next-generation sequencing in the viral diagnostic field. SARS-CoV-2 viral genome sequencing makes it possible to identify mutations in the virus and to track the diffusion of these variants in specific geographic area and in time. Variant sequences help understand how the virus spreads and how it can be contained, as well as for developing more effective vaccines and therapies. Indeed, monitoring the evolution of a virus allows us to quickly detect the potential selection of a super mutation, which can make a virus even more contagious and dangerous in terms of human health consequences. In light of this, in our pilot study, we decided to profile the SARS-CoV-2 genome, recruiting 38 patients divided according to age, sex, vaccination status and symptoms, ascertaining their positivity to the virus. Specific strains of SARS-CoV-2 have been identified and effective through next-generation sequencing. This analysis made it possible to obtain information on the variants of the virus and their spread in the Campania region of the Phlegraean area, in the municipalities of Bacoli, Pozzuoli and Monte di Procida from December 2021 to February 2023 and on the effect of long-term measures COVID-19 in our sample. The advantage of using NGS in diagnosis is the introduction of tests on many genes in a relatively short time and at relatively low costs, with a consequent increase in a precise molecular diagnosis and helps to identify <i>ad personam</i> therapies.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1536953"},"PeriodicalIF":3.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624170","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":"Uncovering a novel binding trench in ERRα: insights from molecular simulations.","authors":"Lamees Hegazy","doi":"10.3389/fmolb.2025.1523932","DOIUrl":"10.3389/fmolb.2025.1523932","url":null,"abstract":"<p><p>Although estrogen-related receptor α (ERRα) holds significant therapeutic potential for treating various disorders, developing selective agonists remains challenging due to the poor pharmacokinetics and limited selectivity of current ligands. This study presents unconstrained molecular dynamics simulations of ERRα bound to an agonist ligand, uncovering dynamic ligand-binding behavior as the ligand shifts between two orientations: one in the orthosteric pocket and another in a newly identified trench adjacent to this site. The free energy landscape reveals that both binding orientations are comparably populated, with an accessible transition pathway between them. The identification of this novel binding trench expands our understanding of ERRα's ligand binding domain, offering new avenues for small-molecule drug discovery and selective modulation of ERRα activity.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1523932"},"PeriodicalIF":3.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624180","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}